rs74315431
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_004738.5(VAPB):c.166C>T(p.Pro56Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P56R) has been classified as Uncertain significance.
Frequency
Consequence
NM_004738.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VAPB | NM_004738.5 | c.166C>T | p.Pro56Ser | missense_variant | 2/6 | ENST00000475243.6 | |
VAPB | NM_001195677.2 | c.166C>T | p.Pro56Ser | missense_variant | 2/3 | ||
VAPB | NR_036633.2 | n.397C>T | non_coding_transcript_exon_variant | 2/4 | |||
VAPB | XR_001754433.3 | n.397C>T | non_coding_transcript_exon_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VAPB | ENST00000475243.6 | c.166C>T | p.Pro56Ser | missense_variant | 2/6 | 1 | NM_004738.5 | P1 | |
VAPB | ENST00000395802.7 | c.166C>T | p.Pro56Ser | missense_variant | 2/3 | 1 | |||
VAPB | ENST00000265619.6 | n.464C>T | non_coding_transcript_exon_variant | 3/6 | 2 | ||||
VAPB | ENST00000520497.1 | c.166C>T | p.Pro56Ser | missense_variant, NMD_transcript_variant | 2/4 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251468Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 19, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2019 | - - |
Amyotrophic lateral sclerosis type 8 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 56 of the VAPB protein (p.Pro56Ser). This variant is present in population databases (rs74315431, gnomAD no frequency). This missense change has been observed in individual(s) with late-onset spinal muscular atrophy, atypical amyotrophic lateral sclerosis, and typical amyotrophic lateral sclerosis (PMID: 15372378, 16187141, 16967488, 24212516, 26566915). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4806). 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 VAPB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects VAPB function (PMID: 15372378, 17804640, 20377183, 21275991, 21933185, 22258555, 22454507, 23771029). For these reasons, this variant has been classified as Pathogenic. - |
Adult-onset proximal spinal muscular atrophy, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at