chr14-73198052-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000021.4(PSEN1):c.791C>T(p.Pro264Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P264P) has been classified as Likely benign.
Frequency
Consequence
NM_000021.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.791C>T | p.Pro264Leu | missense_variant | 8/12 | ENST00000324501.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN1 | ENST00000324501.10 | c.791C>T | p.Pro264Leu | missense_variant | 8/12 | 1 | NM_000021.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250174Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135326
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457910Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 725534
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | PSEN1: PM2, PM5, PS3:Moderate, PS4:Moderate, PP3, PP4 - |
not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 05, 2018 | - - |
Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | This missense change has been observed in individuals with early-onset Alzheimer disease (PMID: 8634712, 16033913, 28350801). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63750301, gnomAD 0.005%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 264 of the PSEN1 protein (p.Pro264Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 11959395, 26438723). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 98080). - |
Mental deterioration;C0497327:Dementia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 06, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at