rs878854975

Variant names:

• chr12-6464888-A-C
• rs878854975
• ENST00000361716.8:c.342T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-6464888-A-C
• chr12-6464888-A-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS1_Very_Strong PM2 PP3 PP5_Very_Strong

The ENST00000361716.8(VAMP1):​c.342T>G​(p.Ser114Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VAMP1 ENST00000361716.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.32
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS1: Transcript ENST00000361716.8 (VAMP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-6464888-A-C is Pathogenic according to our data. Variant chr12-6464888-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 240888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361716.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP1	NM_014231.5	MANE Select	c.340+2T>G		splice_donor intron	N/A	NP_055046.1
	VAMP1	NM_199245.3		c.342T>G	p.Ser114Arg	missense	Exon 4 of 4	NP_954740.1
	VAMP1	NM_001297438.2		c.340+2T>G		splice_donor intron	N/A	NP_001284367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP1	ENST00000361716.8	TSL:1	c.342T>G	p.Ser114Arg	missense	Exon 4 of 4	ENSP00000355122.3
	VAMP1	ENST00000538970.5	TSL:1	n.261T>G		non_coding_transcript_exon	Exon 3 of 3
	VAMP1	ENST00000396308.4	TSL:2 MANE Select	c.340+2T>G		splice_donor intron	N/A	ENSP00000379602.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 30, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 38355957)

Spastic paraplegia Pathogenic:1

Feb 11, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). 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). 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.

Spastic ataxia 1 Pathogenic:1

Sep 07, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Spastic ataxia 1;C5193027:Myasthenic syndrome, congenital, 25, presynaptic Pathogenic:1

Jan 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0067	T
PhyloP100		9.3
ClinPred		0.92	D
GERP RS		5.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 2

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

Other links and lift over

dbSNP: rs878854975; hg19: chr12-6574054; COSMIC: COSV56948213; COSMIC: COSV56948213;