NM_000021.4:c.1292C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000021.4(PSEN1):​c.1292C>T​(p.Ala431Val) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A431E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PSEN1
NM_000021.4 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 7.83
Variant links:
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 12 ACMG points.

PM1
In a region_of_interest Required for interaction with CTNNB1 (size 128) in uniprot entity PSN1_HUMAN there are 38 pathogenic changes around while only 1 benign (97%) in NM_000021.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-73219177-C-A is described in Lovd as [Pathogenic].
PP2
Missense variant in the PSEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 2.1558 (below the threshold of 3.09). Trascript score misZ: 3.0986 (above the threshold of 3.09). GenCC associations: The gene is linked to acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.948
PP5
Variant 14-73219177-C-T is Pathogenic according to our data. Variant chr14-73219177-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 98113.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1, not_provided=1}. Variant chr14-73219177-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PSEN1NM_000021.4 linkc.1292C>T p.Ala431Val missense_variant Exon 12 of 12 ENST00000324501.10 NP_000012.1 P49768-1A0A024R6A3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PSEN1ENST00000324501.10 linkc.1292C>T p.Ala431Val missense_variant Exon 12 of 12 1 NM_000021.4 ENSP00000326366.5 P49768-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Other:1
-
VIB Department of Molecular Genetics, University of Antwerp
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dec 29, 2017
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Frontotemporal dementia Pathogenic:1
Aug 11, 2021
MGZ Medical Genetics Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Pathogenic:1
Dec 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 431 of the PSEN1 protein (p.Ala431Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alzheimer's disease (PMID: 12399144, 27799753; internal data). ClinVar contains an entry for this variant (Variation ID: 98113). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PSEN1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ala431 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16628450, 16897084). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
.;D;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.7
.;H;.;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.6
D;D;D;D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.92
MutPred
0.75
.;Gain of catalytic residue at L432 (P = 2e-04);.;.;.;
MVP
0.99
MPC
1.5
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.79
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs63750083; hg19: chr14-73685885; API