MutationTaster - study a chromosomal position

NEVER press reload or F5 - unless you want to start from the very beginning.
input seems to be ok - now mapping the variant to the different transcripts...
found 9 transcript(s)...
Querying Taster for transcript #1: ENST00000346798
Querying Taster for transcript #2: ENST00000354192
Querying Taster for transcript #3: ENST00000348990
Querying Taster for transcript #4: ENST00000357903
Querying Taster for transcript #5: ENST00000439274
Querying Taster for transcript #6: ENST00000358918
Querying Taster for transcript #7: ENST00000359726
Querying Taster for transcript #8: ENST00000440126
Querying Taster for transcript #9: ENST00000448388
MT speed 0 s - this script 8.033028 s

Results

genesymbol	prediction	probability	model	prediction problem	splicing	ClinVar	amino acid changes	variant type	dbSNP ID	protein length	file
APP	disease_causing_automatic	0.999999473717159	simple_aae		affected	0	D619N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999473717159	simple_aae		affected	0	D638N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999473717159	simple_aae		affected	0	D638N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999473717159	simple_aae		affected	0	D670N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999473717159	simple_aae		affected	0	D584N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999667492239	simple_aae		affected	0	D694N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999895880794	simple_aae		affected	0	D675N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999895880794	simple_aae		affected	0	D676N	single base exchange	rs63749810		show file
APP	disease_causing_automatic	0.999999913646257	simple_aae		affected	0	D563N	single base exchange	rs63749810		show file

Taster files

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999473717159 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000348990

Genbank transcript ID

NM_201414

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.1855G>A
cDNA.2002G>A
g.279282G>A

AA changes

D619N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

619

frameshift

known variant

Reference ID: rs63749810
Allele 'T' was neither found in ExAC nor 1000G.
known disease mutation: rs18101 (pathogenic for Alzheimer disease|ABeta amyloidosis, Iowa type|not provided) dbSNP NCBI variation viewer
known disease mutation at this position, please check HGMD for details (HGMD ID CM011910)

known disease mutation at this position, please check HGMD for details (HGMD ID CM011910)
known disease mutation at this position, please check HGMD for details (HGMD ID CM011910)

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

619

mutated

all conserved

619

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

675

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

611

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
623	623	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
628	628	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
633	633	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
647	647	CONFLICT	D -> E (in Ref. 35; AAA51722).	might get lost (downstream of altered splice site)
651	651	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
652	652	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
656	656	MUTAGEN	S->A: Abolishes chondroitin sulfate binding in L-APP733 isoform.	might get lost (downstream of altered splice site)
656	656	CARBOHYD	O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms.	might get lost (downstream of altered splice site)
659	659	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
663	663	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
667	667	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
671	672	SITE	Cleavage; by beta-secretase.	might get lost (downstream of altered splice site)
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		might get lost (downstream of altered splice site)
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2088 / 2088

position (AA) of stopcodon in wt / mu AA sequence

696 / 696

position of stopcodon in wt / mu cDNA

2235 / 2235

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

148 / 148

chromosome

strand

-1

last intron/exon boundary

2134

theoretical NMD boundary in CDS

1936

length of CDS

2088

coding sequence (CDS) position

1855

cDNA position
(for ins/del: last normal base / first normal base)

2002

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVRVP TTAASTPDAV
DKYLETPGDE NEHAHFQKAK ERLEAKHRER MSQVMREWEE AERQAKNLPK ADKKAVIQHF
QEKVESLEQE AANERQQLVE THMARVEAML NDRRRLALEN YITALQAVPP RPRHVFNMLK
KYVRAEQKDR QHTLKHFEHV RMVDPKKAAQ IRSQVMTHLR VIYERMNQSL SLLYNVPAVA
EEIQDEVDEL LQKEQNYSDD VLANMISEPR ISYGNDALMP SLTETKTTVE LLPVNGEFSL
DDLQPWHSFG ADSVPANTEN EVEPVDARPA ADRGLTTRPG SGLTNIKTEE ISEVKMDAEF
RHDSGYEVHH QKLVFFAEDV GSNKGAIIGL MVGGVVIATV IVITLVMLKK KQYTSIHHGV
VEVDAAVTPE ERHLSKMQQN GYENPTYKFF EQMQN*

mutated AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVRVP TTAASTPDAV
DKYLETPGDE NEHAHFQKAK ERLEAKHRER MSQVMREWEE AERQAKNLPK ADKKAVIQHF
QEKVESLEQE AANERQQLVE THMARVEAML NDRRRLALEN YITALQAVPP RPRHVFNMLK
KYVRAEQKDR QHTLKHFEHV RMVDPKKAAQ IRSQVMTHLR VIYERMNQSL SLLYNVPAVA
EEIQDEVDEL LQKEQNYSDD VLANMISEPR ISYGNDALMP SLTETKTTVE LLPVNGEFSL
DDLQPWHSFG ADSVPANTEN EVEPVDARPA ADRGLTTRPG SGLTNIKTEE ISEVKMDAEF
RHDSGYEVHH QKLVFFAENV GSNKGAIIGL MVGGVVIATV IVITLVMLKK KQYTSIHHGV
VEVDAAVTPE ERHLSKMQQN GYENPTYKFF EQMQN*

speed

1.27 s

All positions are in basepairs (bp) if not explicitly stated differently.
AA/aa: amino acid; CDS: coding sequence; mu: mutated; NMD: nonsense-mediated mRNA decay; nt: nucleotide; wt: wildtype; TGP: 1000 Genomes Project
back to results table

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999473717159 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000439274

Genbank transcript ID

NM_001136130

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.1912G>A
cDNA.1946G>A
g.279282G>A

AA changes

D638N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

638

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

638

mutated

all conserved

638

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

679

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

611

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
647	647	CONFLICT	D -> E (in Ref. 35; AAA51722).	might get lost (downstream of altered splice site)
651	651	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
652	652	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
656	656	CARBOHYD	O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms.	might get lost (downstream of altered splice site)
656	656	MUTAGEN	S->A: Abolishes chondroitin sulfate binding in L-APP733 isoform.	might get lost (downstream of altered splice site)
659	659	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
663	663	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
667	667	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
671	672	SITE	Cleavage; by beta-secretase.	might get lost (downstream of altered splice site)
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		might get lost (downstream of altered splice site)
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2145 / 2145

position (AA) of stopcodon in wt / mu AA sequence

715 / 715

position of stopcodon in wt / mu cDNA

2179 / 2179

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

35 / 35

chromosome

strand

-1

last intron/exon boundary

2078

theoretical NMD boundary in CDS

1993

length of CDS

2145

coding sequence (CDS) position

1912

cDNA position
(for ins/del: last normal base / first normal base)

1946

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV YPELQITNVV EANQPVTIQN WCKRGRKQCK THPHFVIPYR
CLVGEFVSDA LLVPDKCKFL HQERMDVCET HLHWHTVAKE TCSEKSTNLH DYGMLLPCGI
DKFRGVEFVC CPLAEESDNV DSADAEEDDS DVWWGGADTD YADGSEDKVV EVAEEEEVAE
VEEEEADDDE DDEDGDEVEE EAEEPYEEAT ERTTSIATTT TTTTESVEEV VREVCSEQAE
TGPCRAMISR WYFDVTEGKC APFFYGGCGG NRNNFDTEEY CMAVCGSAMS QSLLKTTQEP
LARDPVKLPT TAASTPDAVD KYLETPGDEN EHAHFQKAKE RLEAKHRERM SQVMREWEEA
ERQAKNLPKA DKKAVIQHFQ EKVESLEQEA ANERQQLVET HMARVEAMLN DRRRLALENY
ITALQAVPPR PRHVFNMLKK YVRAEQKDRQ HTLKHFEHVR MVDPKKAAQI RSQVMTHLRV
IYERMNQSLS LLYNVPAVAE EIQDEVDELL QKEQNYSDDV LANMISEPRI SYGNDALMPS
LTETKTTVEL LPVNGEFSLD DLQPWHSFGA DSVPANTENE VEPVDARPAA DRGLTTRPGS
GLTNIKTEEI SEVKMDAEFR HDSGYEVHHQ KLVFFAEDVG SNKGAIIGLM VGGVVIATVI
VITLVMLKKK QYTSIHHGVV EVDAAVTPEE RHLSKMQQNG YENPTYKFFE QMQN*

mutated AA sequence

MLPGLALLLL AAWTARALEV YPELQITNVV EANQPVTIQN WCKRGRKQCK THPHFVIPYR
CLVGEFVSDA LLVPDKCKFL HQERMDVCET HLHWHTVAKE TCSEKSTNLH DYGMLLPCGI
DKFRGVEFVC CPLAEESDNV DSADAEEDDS DVWWGGADTD YADGSEDKVV EVAEEEEVAE
VEEEEADDDE DDEDGDEVEE EAEEPYEEAT ERTTSIATTT TTTTESVEEV VREVCSEQAE
TGPCRAMISR WYFDVTEGKC APFFYGGCGG NRNNFDTEEY CMAVCGSAMS QSLLKTTQEP
LARDPVKLPT TAASTPDAVD KYLETPGDEN EHAHFQKAKE RLEAKHRERM SQVMREWEEA
ERQAKNLPKA DKKAVIQHFQ EKVESLEQEA ANERQQLVET HMARVEAMLN DRRRLALENY
ITALQAVPPR PRHVFNMLKK YVRAEQKDRQ HTLKHFEHVR MVDPKKAAQI RSQVMTHLRV
IYERMNQSLS LLYNVPAVAE EIQDEVDELL QKEQNYSDDV LANMISEPRI SYGNDALMPS
LTETKTTVEL LPVNGEFSLD DLQPWHSFGA DSVPANTENE VEPVDARPAA DRGLTTRPGS
GLTNIKTEEI SEVKMDAEFR HDSGYEVHHQ KLVFFAENVG SNKGAIIGLM VGGVVIATVI
VITLVMLKKK QYTSIHHGVV EVDAAVTPEE RHLSKMQQNG YENPTYKFFE QMQN*

speed

1.16 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999473717159 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000359726

Genbank transcript ID

N/A

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.1912G>A
cDNA.2112G>A
g.279282G>A

AA changes

D638N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

638

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

638

mutated

all conserved

638

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

675

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

601

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
647	647	CONFLICT	D -> E (in Ref. 35; AAA51722).	might get lost (downstream of altered splice site)
651	651	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
652	652	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
656	656	CARBOHYD	O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms.	might get lost (downstream of altered splice site)
656	656	MUTAGEN	S->A: Abolishes chondroitin sulfate binding in L-APP733 isoform.	might get lost (downstream of altered splice site)
659	659	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
663	663	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
667	667	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
671	672	SITE	Cleavage; by beta-secretase.	might get lost (downstream of altered splice site)
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		might get lost (downstream of altered splice site)
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2145 / 2145

position (AA) of stopcodon in wt / mu AA sequence

715 / 715

position of stopcodon in wt / mu cDNA

2345 / 2345

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

201 / 201

chromosome

strand

-1

last intron/exon boundary

2244

theoretical NMD boundary in CDS

1993

length of CDS

2145

coding sequence (CDS) position

1912

cDNA position
(for ins/del: last normal base / first normal base)

2112

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVRVS QSLLKTTQEP
LARDPVKLPT TAASTPDAVD KYLETPGDEN EHAHFQKAKE RLEAKHRERM SQVMREWEEA
ERQAKNLPKA DKKAVIQHFQ EKVESLEQEA ANERQQLVET HMARVEAMLN DRRRLALENY
ITALQAVPPR PRHVFNMLKK YVRAEQKDRQ HTLKHFEHVR MVDPKKAAQI RSQVMTHLRV
IYERMNQSLS LLYNVPAVAE EIQDEVDELL QKEQNYSDDV LANMISEPRI SYGNDALMPS
LTETKTTVEL LPVNGEFSLD DLQPWHSFGA DSVPANTENE VEPVDARPAA DRGLTTRPGS
GLTNIKTEEI SEVKMDAEFR HDSGYEVHHQ KLVFFAEDVG SNKGAIIGLM VGGVVIATVI
VITLVMLKKK QYTSIHHGVV EVDAAVTPEE RHLSKMQQNG YENPTYKFFE QMQN*

mutated AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVRVS QSLLKTTQEP
LARDPVKLPT TAASTPDAVD KYLETPGDEN EHAHFQKAKE RLEAKHRERM SQVMREWEEA
ERQAKNLPKA DKKAVIQHFQ EKVESLEQEA ANERQQLVET HMARVEAMLN DRRRLALENY
ITALQAVPPR PRHVFNMLKK YVRAEQKDRQ HTLKHFEHVR MVDPKKAAQI RSQVMTHLRV
IYERMNQSLS LLYNVPAVAE EIQDEVDELL QKEQNYSDDV LANMISEPRI SYGNDALMPS
LTETKTTVEL LPVNGEFSLD DLQPWHSFGA DSVPANTENE VEPVDARPAA DRGLTTRPGS
GLTNIKTEEI SEVKMDAEFR HDSGYEVHHQ KLVFFAENVG SNKGAIIGLM VGGVVIATVI
VITLVMLKKK QYTSIHHGVV EVDAAVTPEE RHLSKMQQNG YENPTYKFFE QMQN*

speed

0.97 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999473717159 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000440126

Genbank transcript ID

NM_001136016

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.2008G>A
cDNA.2165G>A
g.279282G>A

AA changes

D670N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

670

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

670

mutated

all conserved

670

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

675

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

620

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
671	672	SITE	Cleavage; by beta-secretase.	might get lost (downstream of altered splice site)
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		might get lost (downstream of altered splice site)
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2241 / 2241

position (AA) of stopcodon in wt / mu AA sequence

747 / 747

position of stopcodon in wt / mu cDNA

2398 / 2398

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

158 / 158

chromosome

strand

-1

last intron/exon boundary

2297

theoretical NMD boundary in CDS

2089

length of CDS

2241

coding sequence (CDS) position

2008

cDNA position
(for ins/del: last normal base / first normal base)

2165

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MDQLEDLLVL FINYVPTDGN AGLLAEPQIA MFCGRLNMHM NVQNGKWDSD PSGTKTCIDT
KEGILQYCQE VYPELQITNV VEANQPVTIQ NWCKRGRKQC KTHPHFVIPY RCLVGEFVSD
ALLVPDKCKF LHQERMDVCE THLHWHTVAK ETCSEKSTNL HDYGMLLPCG IDKFRGVEFV
CCPLAEESDN VDSADAEEDD SDVWWGGADT DYADGSEDKV VEVAEEEEVA EVEEEEADDD
EDDEDGDEVE EEAEEPYEEA TERTTSIATT TTTTTESVEE VVREVCSEQA ETGPCRAMIS
RWYFDVTEGK CAPFFYGGCG GNRNNFDTEE YCMAVCGSAI PTTAASTPDA VDKYLETPGD
ENEHAHFQKA KERLEAKHRE RMSQVMREWE EAERQAKNLP KADKKAVIQH FQEKVESLEQ
EAANERQQLV ETHMARVEAM LNDRRRLALE NYITALQAVP PRPRHVFNML KKYVRAEQKD
RQHTLKHFEH VRMVDPKKAA QIRSQVMTHL RVIYERMNQS LSLLYNVPAV AEEIQDEVDE
LLQKEQNYSD DVLANMISEP RISYGNDALM PSLTETKTTV ELLPVNGEFS LDDLQPWHSF
GADSVPANTE NEVEPVDARP AADRGLTTRP GSGLTNIKTE EISEVKMDAE FRHDSGYEVH
HQKLVFFAED VGSNKGAIIG LMVGGVVIAT VIVITLVMLK KKQYTSIHHG VVEVDAAVTP
EERHLSKMQQ NGYENPTYKF FEQMQN*

mutated AA sequence

MDQLEDLLVL FINYVPTDGN AGLLAEPQIA MFCGRLNMHM NVQNGKWDSD PSGTKTCIDT
KEGILQYCQE VYPELQITNV VEANQPVTIQ NWCKRGRKQC KTHPHFVIPY RCLVGEFVSD
ALLVPDKCKF LHQERMDVCE THLHWHTVAK ETCSEKSTNL HDYGMLLPCG IDKFRGVEFV
CCPLAEESDN VDSADAEEDD SDVWWGGADT DYADGSEDKV VEVAEEEEVA EVEEEEADDD
EDDEDGDEVE EEAEEPYEEA TERTTSIATT TTTTTESVEE VVREVCSEQA ETGPCRAMIS
RWYFDVTEGK CAPFFYGGCG GNRNNFDTEE YCMAVCGSAI PTTAASTPDA VDKYLETPGD
ENEHAHFQKA KERLEAKHRE RMSQVMREWE EAERQAKNLP KADKKAVIQH FQEKVESLEQ
EAANERQQLV ETHMARVEAM LNDRRRLALE NYITALQAVP PRPRHVFNML KKYVRAEQKD
RQHTLKHFEH VRMVDPKKAA QIRSQVMTHL RVIYERMNQS LSLLYNVPAV AEEIQDEVDE
LLQKEQNYSD DVLANMISEP RISYGNDALM PSLTETKTTV ELLPVNGEFS LDDLQPWHSF
GADSVPANTE NEVEPVDARP AADRGLTTRP GSGLTNIKTE EISEVKMDAE FRHDSGYEVH
HQKLVFFAEN VGSNKGAIIG LMVGGVVIAT VIVITLVMLK KKQYTSIHHG VVEVDAAVTP
EERHLSKMQQ NGYENPTYKF FEQMQN*

speed

0.68 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999473717159 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000448388

Genbank transcript ID

NM_001136131

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.1750G>A
cDNA.1942G>A
g.279282G>A

AA changes

D584N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

584

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

584

mutated

all conserved

584

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

685

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

611

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
614	614	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
623	623	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
628	628	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
633	633	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
647	647	CONFLICT	D -> E (in Ref. 35; AAA51722).	might get lost (downstream of altered splice site)
651	651	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
652	652	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
656	656	MUTAGEN	S->A: Abolishes chondroitin sulfate binding in L-APP733 isoform.	might get lost (downstream of altered splice site)
656	656	CARBOHYD	O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms.	might get lost (downstream of altered splice site)
659	659	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
663	663	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
667	667	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
671	672	SITE	Cleavage; by beta-secretase.	might get lost (downstream of altered splice site)
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		might get lost (downstream of altered splice site)
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

1983 / 1983

position (AA) of stopcodon in wt / mu AA sequence

661 / 661

position of stopcodon in wt / mu cDNA

2175 / 2175

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

193 / 193

chromosome

strand

-1

last intron/exon boundary

2074

theoretical NMD boundary in CDS

1831

length of CDS

1983

coding sequence (CDS) position

1750

cDNA position
(for ins/del: last normal base / first normal base)

1942

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MFCGRLNMHM NVQNGKWDSD PSGTKTCIDT KEGILQYCQE VYPELQITNV VEANQPVTIQ
NWCKRGRKQC KTHPHFVIPY RCLVGEFVSD ALLVPDKCKF LHQERMDVCE THLHWHTVAK
ETCSEKSTNL HDYGMLLPCG IDKFRGVEFV CCPLAEESDN VDSADAEEDD SDVWWGGADT
DYADGSEDKV VEVAEEEEVA EVEEEEADDD EDDEDGDEVE EEAEEPYEEA TERTTSIATT
TTTTTESVEE VVRVPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM
REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR
LALENYITAL QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV
MTHLRVIYER MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN
DALMPSLTET KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL
TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV
VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
*

mutated AA sequence

MFCGRLNMHM NVQNGKWDSD PSGTKTCIDT KEGILQYCQE VYPELQITNV VEANQPVTIQ
NWCKRGRKQC KTHPHFVIPY RCLVGEFVSD ALLVPDKCKF LHQERMDVCE THLHWHTVAK
ETCSEKSTNL HDYGMLLPCG IDKFRGVEFV CCPLAEESDN VDSADAEEDD SDVWWGGADT
DYADGSEDKV VEVAEEEEVA EVEEEEADDD EDDEDGDEVE EEAEEPYEEA TERTTSIATT
TTTTTESVEE VVRVPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM
REWEEAERQA KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR
LALENYITAL QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV
MTHLRVIYER MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN
DALMPSLTET KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL
TTRPGSGLTN IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAENVGSNKG AIIGLMVGGV
VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN
*

speed

1.14 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999667492239 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000346798

Genbank transcript ID

NM_000484

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.2080G>A
cDNA.2114G>A
g.279282G>A

AA changes

D694N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

694

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

694

mutated

all conserved

694

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

685

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

611

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	lost
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	lost
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2313 / 2313

position (AA) of stopcodon in wt / mu AA sequence

771 / 771

position of stopcodon in wt / mu cDNA

2347 / 2347

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

35 / 35

chromosome

strand

-1

last intron/exon boundary

2246

theoretical NMD boundary in CDS

2161

length of CDS

2313

coding sequence (CDS) position

2080

cDNA position
(for ins/del: last normal base / first normal base)

2114

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAEDVGSNKG AIIGLMVGGV VIATVIVITL
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN *

mutated AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEVEPV DARPAADRGL TTRPGSGLTN
IKTEEISEVK MDAEFRHDSG YEVHHQKLVF FAENVGSNKG AIIGLMVGGV VIATVIVITL
VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYENP TYKFFEQMQN *

speed

1.20 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999895880794 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000357903

Genbank transcript ID

NM_201413

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.2023G>A
cDNA.2190G>A
g.279282G>A

AA changes

D675N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

675

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

675

mutated

all conserved

675

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

675

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

620

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		lost
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2256 / 2256

position (AA) of stopcodon in wt / mu AA sequence

752 / 752

position of stopcodon in wt / mu cDNA

2423 / 2423

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

168 / 168

chromosome

strand

-1

last intron/exon boundary

2322

theoretical NMD boundary in CDS

2104

length of CDS

2256

coding sequence (CDS) position

2023

cDNA position
(for ins/del: last normal base / first normal base)

2190

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAIPTTAA STPDAVDKYL
ETPGDENEHA HFQKAKERLE AKHRERMSQV MREWEEAERQ AKNLPKADKK AVIQHFQEKV
ESLEQEAANE RQQLVETHMA RVEAMLNDRR RLALENYITA LQAVPPRPRH VFNMLKKYVR
AEQKDRQHTL KHFEHVRMVD PKKAAQIRSQ VMTHLRVIYE RMNQSLSLLY NVPAVAEEIQ
DEVDELLQKE QNYSDDVLAN MISEPRISYG NDALMPSLTE TKTTVELLPV NGEFSLDDLQ
PWHSFGADSV PANTENEVEP VDARPAADRG LTTRPGSGLT NIKTEEISEV KMDAEFRHDS
GYEVHHQKLV FFAEDVGSNK GAIIGLMVGG VVIATVIVIT LVMLKKKQYT SIHHGVVEVD
AAVTPEERHL SKMQQNGYEN PTYKFFEQMQ N*

mutated AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAIPTTAA STPDAVDKYL
ETPGDENEHA HFQKAKERLE AKHRERMSQV MREWEEAERQ AKNLPKADKK AVIQHFQEKV
ESLEQEAANE RQQLVETHMA RVEAMLNDRR RLALENYITA LQAVPPRPRH VFNMLKKYVR
AEQKDRQHTL KHFEHVRMVD PKKAAQIRSQ VMTHLRVIYE RMNQSLSLLY NVPAVAEEIQ
DEVDELLQKE QNYSDDVLAN MISEPRISYG NDALMPSLTE TKTTVELLPV NGEFSLDDLQ
PWHSFGADSV PANTENEVEP VDARPAADRG LTTRPGSGLT NIKTEEISEV KMDAEFRHDS
GYEVHHQKLV FFAENVGSNK GAIIGLMVGG VVIATVIVIT LVMLKKKQYT SIHHGVVEVD
AAVTPEERHL SKMQQNGYEN PTYKFFEQMQ N*

speed

1.26 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999895880794 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000358918

Genbank transcript ID

NM_001204301

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.2026G>A
cDNA.2226G>A
g.279282G>A

AA changes

D676N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

676

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

676

mutated

all conserved

676

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

674

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

611

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
674	677	TURN		lost
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	lost
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

2259 / 2259

position (AA) of stopcodon in wt / mu AA sequence

753 / 753

position of stopcodon in wt / mu cDNA

2459 / 2459

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

201 / 201

chromosome

strand

-1

last intron/exon boundary

2358

theoretical NMD boundary in CDS

2107

length of CDS

2259

coding sequence (CDS) position

2026

cDNA position
(for ins/del: last normal base / first normal base)

2226

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEGSGL TNIKTEEISE VKMDAEFRHD
SGYEVHHQKL VFFAEDVGSN KGAIIGLMVG GVVIATVIVI TLVMLKKKQY TSIHHGVVEV
DAAVTPEERH LSKMQQNGYE NPTYKFFEQM QN*

mutated AA sequence

MLPGLALLLL AAWTARALEV PTDGNAGLLA EPQIAMFCGR LNMHMNVQNG KWDSDPSGTK
TCIDTKEGIL QYCQEVYPEL QITNVVEANQ PVTIQNWCKR GRKQCKTHPH FVIPYRCLVG
EFVSDALLVP DKCKFLHQER MDVCETHLHW HTVAKETCSE KSTNLHDYGM LLPCGIDKFR
GVEFVCCPLA EESDNVDSAD AEEDDSDVWW GGADTDYADG SEDKVVEVAE EEEVAEVEEE
EADDDEDDED GDEVEEEAEE PYEEATERTT SIATTTTTTT ESVEEVVREV CSEQAETGPC
RAMISRWYFD VTEGKCAPFF YGGCGGNRNN FDTEEYCMAV CGSAMSQSLL KTTQEPLARD
PVKLPTTAAS TPDAVDKYLE TPGDENEHAH FQKAKERLEA KHRERMSQVM REWEEAERQA
KNLPKADKKA VIQHFQEKVE SLEQEAANER QQLVETHMAR VEAMLNDRRR LALENYITAL
QAVPPRPRHV FNMLKKYVRA EQKDRQHTLK HFEHVRMVDP KKAAQIRSQV MTHLRVIYER
MNQSLSLLYN VPAVAEEIQD EVDELLQKEQ NYSDDVLANM ISEPRISYGN DALMPSLTET
KTTVELLPVN GEFSLDDLQP WHSFGADSVP ANTENEGSGL TNIKTEEISE VKMDAEFRHD
SGYEVHHQKL VFFAENVGSN KGAIIGLMVG GVVIATVIVI TLVMLKKKQY TSIHHGVVEV
DAAVTPEERH LSKMQQNGYE NPTYKFFEQM QN*

speed

1.15 s

mutation t@sting

documentation

Prediction

disease causing

Model: simple_aae, prob: 0.999999913646257 (classification due to ClinVar, real probability is shown anyway) (explain)

Summary

amino acid sequence changed
known disease mutation at this position (HGMD CM011910)
known disease mutation: rs18101 (pathogenic)
protein features (might be) affected
splice site changes

hyperlink

analysed issue

analysis result

name of alteration

no title

alteration (phys. location)

chr21:27264165C>TN/A show variant in all transcripts IGV

HGNC symbol

APP

Ensembl transcript ID

ENST00000354192

Genbank transcript ID

NM_001136129

UniProt peptide

P05067

alteration type

single base exchange

alteration region

CDS

DNA changes

c.1687G>A
cDNA.1814G>A
g.279282G>A

AA changes

D563N Score: 23 explain score(s)

position(s) of altered AA
if AA alteration in CDS

563

frameshift

known variant

regulatory features

H3K36me3, Histone, Histone 3 Lysine 36 Tri-Methylation

phyloP / phastCons

	PhyloP	PhastCons
(flanking)	4.745	1
	4.053	1
(flanking)	2.268	1

explain score(s) and/or inspect your position(s) in in UCSC Genome Browser

splice sites

effect	gDNA position	score	wt detection sequence	exon-intron border
Acc marginally increased	279277	wt: 0.5630 / mu: 0.6058 (marginal change - not scored)	wt: TGTTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACA mu: TGTTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACA	ttgc\|AGAA
Acc increased	279279	wt: 0.62 / mu: 0.77	wt: TTTTCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAA mu: TTTTCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAA	gcag\|AAGA
Donor marginally increased	279279	wt: 0.6197 / mu: 0.6806 (marginal change - not scored)	wt: TTGCAGAAGATGTGG mu: TTGCAGAAAATGTGG	GCAG\|aaga
Donor gained	279278	0.58	mu: TTTGCAGAAAATGTG	TGCA\|gaaa
Donor gained	279277	0.56	mu: CTTTGCAGAAAATGT	TTGC\|agaa

distance from splice site

Kozak consensus sequence altered?

N/A

conservation
protein level for non-synonymous changes

species

match

gene

alignment

Human

563

mutated

all conserved

563

Ptroglodytes

all identical

ENSPTRG00000013811

694

Mmulatta

all identical

ENSMMUG00000014384

694

Fcatus

all identical

ENSFCAG00000001556

675

Mmusculus

all identical

ENSMUSG00000022892

619

Ggallus

all identical

ENSGALG00000015770

675

Trubripes

all identical

ENSTRUG00000010470

688

Drerio

all identical

ENSDARG00000055543

675

Dmelanogaster

no alignment

FBgn0000108

n/a

Celegans

not conserved

C42D8.8

612

Xtropicalis

all conserved

ENSXETG00000013612

695

protein features

start (aa)	end (aa)	feature	details
18	699	TOPO_DOM	Extracellular (Potential).	lost
552	566	HELIX		lost
571	571	CARBOHYD	N-linked (GlcNAc...) (Probable).	might get lost (downstream of altered splice site)
614	614	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
623	623	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
628	628	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
633	633	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
647	647	CONFLICT	D -> E (in Ref. 35; AAA51722).	might get lost (downstream of altered splice site)
651	651	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
652	652	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
656	656	CARBOHYD	O-linked (Xyl...) (chondroitin sulfate); in L-APP isoforms.	might get lost (downstream of altered splice site)
656	656	MUTAGEN	S->A: Abolishes chondroitin sulfate binding in L-APP733 isoform.	might get lost (downstream of altered splice site)
659	659	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
663	663	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
667	667	CARBOHYD	O-linked (GalNAc...) (Probable).	might get lost (downstream of altered splice site)
671	672	SITE	Cleavage; by beta-secretase.	might get lost (downstream of altered splice site)
672	673	SITE	Cleavage; by caspase-6; when associated with variant 670-N-L-671.	might get lost (downstream of altered splice site)
674	677	TURN		might get lost (downstream of altered splice site)
676	676	MUTAGEN	R->G: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
677	677	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
679	679	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
679	682	STRAND		might get lost (downstream of altered splice site)
681	681	MUTAGEN	Y->F: 60-70% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
681	681	METAL	Copper or zinc 2 (Probable).	might get lost (downstream of altered splice site)
683	685	STRAND		might get lost (downstream of altered splice site)
684	684	MUTAGEN	H->R: Only 23% zinc-induced beta-APP (28) peptide aggregation.	might get lost (downstream of altered splice site)
684	684	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
685	685	METAL	Copper or zinc 2.	might get lost (downstream of altered splice site)
687	688	SITE	Cleavage; by alpha-secretase.	might get lost (downstream of altered splice site)
688	691	STRAND		might get lost (downstream of altered splice site)
688	711	PEPTIDE	P3(40). /FTId=PRO_0000000096.	might get lost (downstream of altered splice site)
688	713	PEPTIDE	P3(42). /FTId=PRO_0000000095.	might get lost (downstream of altered splice site)
690	691	SITE	Cleavage; by theta-secretase.	might get lost (downstream of altered splice site)
695	697	HELIX		might get lost (downstream of altered splice site)
697	697	CARBOHYD	O-linked (GalNAc...).	might get lost (downstream of altered splice site)
698	700	STRAND		might get lost (downstream of altered splice site)
700	723	TRANSMEM	Helical; (Potential).	might get lost (downstream of altered splice site)
702	705	STRAND		might get lost (downstream of altered splice site)
704	704	SITE	Implicated in free radical propagation (By similarity).	might get lost (downstream of altered splice site)
704	704	MUTAGEN	G->V: Reduced protein oxidation. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
706	706	SITE	Susceptible to oxidation.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->L: Reduced lipid peroxidation inhibition.	might get lost (downstream of altered splice site)
706	706	MUTAGEN	M->V: No free radical production. No hippocampal neuron toxicity.	might get lost (downstream of altered splice site)
707	712	STRAND		might get lost (downstream of altered splice site)
711	712	SITE	Cleavage; by gamma-secretase; site 1.	might get lost (downstream of altered splice site)
713	714	SITE	Cleavage; by gamma-secretase; site 2.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->F,G,I: Increased beta-APP42/beta-APP40 ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->C,S: Unchanged beta-APP42/total APP- beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->K: Decreased beta-APP42/total APP-beta ratio.	might get lost (downstream of altered splice site)
717	717	MUTAGEN	V->M: Increased beta-APP42/beta-APP40 ratio. No change in apoptosis after caspase cleavage.	might get lost (downstream of altered splice site)
720	721	SITE	Cleavage; by gamma-secretase; site 3.	might get lost (downstream of altered splice site)
724	724	CONFLICT	Missing (in Ref. 22; AAB26263/AAB26264).	might get lost (downstream of altered splice site)
724	734	MOTIF	Basolateral sorting signal.	might get lost (downstream of altered splice site)
724	770	TOPO_DOM	Cytoplasmic (Potential).	might get lost (downstream of altered splice site)
728	728	MUTAGEN	Y->A: No effect on APBA1 nor APBB1 binding. Greatly reduces the binding to APPBP2. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
729	729	MOD_RES	Phosphothreonine (By similarity).	might get lost (downstream of altered splice site)
730	730	MOD_RES	Phosphoserine; by APP-kinase I (By similarity).	might get lost (downstream of altered splice site)
731	731	CONFLICT	I -> N (in Ref. 22; AAB26263/AAB26264/ AAB26265).	might get lost (downstream of altered splice site)
732	751	REGION	Interaction with G(o)-alpha.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->N: No effect on FADD-induced apoptosis.	might get lost (downstream of altered splice site)
739	739	MUTAGEN	D->A: No cleavage by caspases during apoptosis.	might get lost (downstream of altered splice site)
739	740	SITE	Cleavage; by caspase-6, caspase-8 or caspase-9.	might get lost (downstream of altered splice site)
743	743	MOD_RES	Phosphothreonine; by CDK5 and MAPK10.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->A: Greatly reduces the binding to SHC1 and APBB family members; no effect on NGF-stimulated neurite extension.	might get lost (downstream of altered splice site)
743	743	MUTAGEN	T->E: Reduced NGF-stimulated neurite extension. No effect on APP maturation.	might get lost (downstream of altered splice site)
744	754	HELIX		might get lost (downstream of altered splice site)
755	758	STRAND		might get lost (downstream of altered splice site)
756	756	MUTAGEN	G->A: APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->G: Loss of binding to MAPK8IP1, APBA1, APBB1, APPBP2 and SHC1.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
757	757	MOD_RES	Phosphotyrosine; by ABL1 (By similarity).	might get lost (downstream of altered splice site)
757	757	MUTAGEN	Y->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
757	757	CONFLICT	Y -> S (in Ref. 30; AAA35540).	might get lost (downstream of altered splice site)
759	759	MUTAGEN	N->A: No binding to APBA1, no effect on APBB1 binding. Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
759	762	MOTIF	NPXY motif; contains endocytosis signal.	might get lost (downstream of altered splice site)
760	760	MUTAGEN	P->A: Little APP internalization. Reduced beta-APP42 secretion.	might get lost (downstream of altered splice site)
762	762	MOD_RES	Phosphotyrosine.	might get lost (downstream of altered splice site)
762	762	MUTAGEN	Y->A: Loss of binding to APBA1 and APBB1. APP internalization unchanged. No change in beta-APP42 secretion.	might get lost (downstream of altered splice site)
763	765	STRAND		might get lost (downstream of altered splice site)

length of protein

normal

AA sequence altered

yes

position of stopcodon in wt / mu CDS

1920 / 1920

position (AA) of stopcodon in wt / mu AA sequence

640 / 640

position of stopcodon in wt / mu cDNA

2047 / 2047

poly(A) signal

N/A

conservation
nucleotide level for all changes - no scoring up to now

N/A

position of start ATG in wt / mu cDNA

128 / 128

chromosome

strand

-1

last intron/exon boundary

1946

theoretical NMD boundary in CDS

1768

length of CDS

1920

coding sequence (CDS) position

1687

cDNA position
(for ins/del: last normal base / first normal base)

1814

gDNA position
(for ins/del: last normal base / first normal base)

279282

chromosomal position
(for ins/del: last normal base / first normal base)

27264165

original gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered gDNA sequence snippet

TCAAGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

original cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAGATGTGGGTTCAAACAAAGGT

altered cDNA sequence snippet

AATTGGTGTTCTTTGCAGAAAATGTGGGTTCAAACAAAGGT

wildtype AA sequence

MLPGLALLLL AAWTARALEV YPELQITNVV EANQPVTIQN WCKRGRKQCK THPHFVIPYR
CLVGEFVSDA LLVPDKCKFL HQERMDVCET HLHWHTVAKE TCSEKSTNLH DYGMLLPCGI
DKFRGVEFVC CPLAEESDNV DSADAEEDDS DVWWGGADTD YADGSEDKVV EVAEEEEVAE
VEEEEADDDE DDEDGDEVEE EAEEPYEEAT ERTTSIATTT TTTTESVEEV VRVPTTAAST
PDAVDKYLET PGDENEHAHF QKAKERLEAK HRERMSQVMR EWEEAERQAK NLPKADKKAV
IQHFQEKVES LEQEAANERQ QLVETHMARV EAMLNDRRRL ALENYITALQ AVPPRPRHVF
NMLKKYVRAE QKDRQHTLKH FEHVRMVDPK KAAQIRSQVM THLRVIYERM NQSLSLLYNV
PAVAEEIQDE VDELLQKEQN YSDDVLANMI SEPRISYGND ALMPSLTETK TTVELLPVNG
EFSLDDLQPW HSFGADSVPA NTENEVEPVD ARPAADRGLT TRPGSGLTNI KTEEISEVKM
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV IATVIVITLV MLKKKQYTSI
HHGVVEVDAA VTPEERHLSK MQQNGYENPT YKFFEQMQN*

mutated AA sequence

MLPGLALLLL AAWTARALEV YPELQITNVV EANQPVTIQN WCKRGRKQCK THPHFVIPYR
CLVGEFVSDA LLVPDKCKFL HQERMDVCET HLHWHTVAKE TCSEKSTNLH DYGMLLPCGI
DKFRGVEFVC CPLAEESDNV DSADAEEDDS DVWWGGADTD YADGSEDKVV EVAEEEEVAE
VEEEEADDDE DDEDGDEVEE EAEEPYEEAT ERTTSIATTT TTTTESVEEV VRVPTTAAST
PDAVDKYLET PGDENEHAHF QKAKERLEAK HRERMSQVMR EWEEAERQAK NLPKADKKAV
IQHFQEKVES LEQEAANERQ QLVETHMARV EAMLNDRRRL ALENYITALQ AVPPRPRHVF
NMLKKYVRAE QKDRQHTLKH FEHVRMVDPK KAAQIRSQVM THLRVIYERM NQSLSLLYNV
PAVAEEIQDE VDELLQKEQN YSDDVLANMI SEPRISYGND ALMPSLTETK TTVELLPVNG
EFSLDDLQPW HSFGADSVPA NTENEVEPVD ARPAADRGLT TRPGSGLTNI KTEEISEVKM
DAEFRHDSGY EVHHQKLVFF AENVGSNKGA IIGLMVGGVV IATVIVITLV MLKKKQYTSI
HHGVVEVDAA VTPEERHLSK MQQNGYENPT YKFFEQMQN*

speed

1.34 s

MutationTaster - study a chromosomal position

Results

Taster files

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

mutation t@sting

Prediction

disease causing

Problems