12-6464888-A-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PVS1: Splicing 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
• PP3: Splicing scoreres supports a deletorius 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 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	UniProt
VAMP1	NM_014231.5	c.340+2T>G		splice_donor_variant		ENST00000396308.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP1	ENST00000396308.4	c.340+2T>G		splice_donor_variant		2	NM_014231.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2023	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 (Bourassa et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22958904, 27957547, 11774073) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2017	- -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	D;D;D;D
ClinPred		0.92	D
GERP RS		5.7

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

Publications

LitVar

Other links and lift over

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