rs661
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_000021.4(PSEN1):c.1229G>A(p.Cys410Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
PSEN1
NM_000021.4 missense
NM_000021.4 missense
Scores
14
1
1
Clinical Significance
Conservation
PhyloP100: 9.54
Genes affected
PSEN1 (HGNC:9508): (presenilin 1) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000021.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, PSEN1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
?
Variant 14-73217225-G-A is Pathogenic according to our data. Variant chr14-73217225-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18127.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-73217225-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.1229G>A | p.Cys410Tyr | missense_variant | 11/12 | ENST00000324501.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN1 | ENST00000324501.10 | c.1229G>A | p.Cys410Tyr | missense_variant | 11/12 | 1 | NM_000021.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2017 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects protein function (PMID: 27100199, 24011544, 27100200, 23843529, 20484632, 27930341, 25741723, 22115042, 9680315, 17288597, 21559374, 9196071). This variant has been reported in families affected with early onset Alzheimer's disease (PMID: 17545141, 17553989, 24880964). This variant has also been to found segregate with early onset Alzheimer's disease in several families (PMID: 7596406, 8634712). ClinVar contains an entry for this variant (Variation ID: 18127). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 410 of the PSEN1 protein (p.Cys410Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. - |
Alzheimer disease 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 29, 1995 | - - |
not provided Other:1
not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;D;.;.
Vest4
MutPred
0.81
.;Gain of catalytic residue at A413 (P = 0.0014);.;.;.;
MVP
MPC
1.9
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at