rs878854975
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014231.5(VAMP1):c.340+2T>G variant causes a splice donor 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. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
VAMP1
NM_014231.5 splice_donor
NM_014231.5 splice_donor
Scores
2
3
3
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
VAMP1 (HGNC:12642): (vesicle associated membrane protein 1) Synapotobrevins, syntaxins, and the synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Mutations in this gene are associated with autosomal dominant spastic ataxia 1. Multiple alternative splice variants have been described, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2014]
TAPBPL (HGNC:30683): (TAP binding protein like) Tapasin, or TAPBP (MIM 601962), is a member of the variable-constant Ig superfamily that links major histocompatibility complex (MHC) class I molecules to the transporter associated with antigen processing (TAP; see MIM 170260) in the endoplasmic reticulum (ER). The TAPBP gene is located near the MHC complex on chromosome 6p21.3. TAPBPL is a member of the Ig superfamily that is localized on chromosome 12p13.3, a region somewhat paralogous to the MHC.[supplied by OMIM, Mar 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.9, offset of -4, new splice context is: attGTaagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-6464888-A-C is Pathogenic according to our data. Variant chr12-6464888-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 240888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VAMP1 | NM_014231.5 | c.340+2T>G | splice_donor_variant | ENST00000396308.4 | NP_055046.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VAMP1 | ENST00000396308.4 | c.340+2T>G | splice_donor_variant | 2 | NM_014231.5 | ENSP00000379602 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2024 | Published functional studies demonstrate that this variant affects a critical donor site for the splicing of VAMP1 isoforms and results in an in-frame addition of 33 amino acids (PMID: 22958904); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27957547, 11774073, 22958904) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 30, 2017 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 11, 2016 | In summary, this variant has been reported to segregate with disease in affected families and to alter mRNA splicing in functional studies. For these reasons, this change has been classified as Pathogenic. Experimental studies have shown that this intronic change leads to aberrant splicing of intron 4, which is predicted to lead to a truncated protein product relative to the major VAMP1 neuronal isoform (PMID: 22958904). This variant has been reported in many (>10) individuals affected with spastic ataxia. In addition, it has been shown to segregate with disease in 4 large families with origins in Newfoundland, Cananda (PMID: 22958904). This sequence change affects a donor splice site in intron 4 of the VAMP1 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. - |
Spastic ataxia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 07, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MutationTaster
Benign
D;D;D;D
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at