rs1555813002
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_004738.5(VAPB):c.194C>T(p.Ala65Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65T) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
VAPB
NM_004738.5 missense
NM_004738.5 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 6.17
Genes affected
VAPB (HGNC:12649): (VAMP associated protein B and C) The protein encoded by this gene is a type IV membrane protein found in plasma and intracellular vesicle membranes. The encoded protein is found as a homodimer and as a heterodimer with VAPA. This protein also can interact with VAMP1 and VAMP2 and may be involved in vesicle trafficking. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a domain MSP (size 117) in uniprot entity VAPB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004738.5
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2730673).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VAPB | NM_004738.5 | c.194C>T | p.Ala65Val | missense_variant | 2/6 | ENST00000475243.6 | |
VAPB | NM_001195677.2 | c.194C>T | p.Ala65Val | missense_variant | 2/3 | ||
VAPB | NR_036633.2 | n.425C>T | non_coding_transcript_exon_variant | 2/4 | |||
VAPB | XR_001754433.3 | n.425C>T | non_coding_transcript_exon_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VAPB | ENST00000475243.6 | c.194C>T | p.Ala65Val | missense_variant | 2/6 | 1 | NM_004738.5 | P1 | |
VAPB | ENST00000395802.7 | c.194C>T | p.Ala65Val | missense_variant | 2/3 | 1 | |||
VAPB | ENST00000265619.6 | n.492C>T | non_coding_transcript_exon_variant | 3/6 | 2 | ||||
VAPB | ENST00000520497.1 | c.194C>T | p.Ala65Val | missense_variant, NMD_transcript_variant | 2/4 | 2 |
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: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 8;C1854058:Adult-onset proximal spinal muscular atrophy, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2018 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with VAPB-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 65 of the VAPB protein (p.Ala65Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;D
Sift4G
Benign
T;D
Polyphen
B;B
Vest4
MutPred
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
MPC
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