ENST00000538970.5:n.459C>A

Variant names:

• chr12-6464690-G-T
• rs1034969
• ENST00000538970.5:n.459C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000538970.5(VAMP1):​n.459C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,491,888 control chromosomes in the GnomAD database, including 71,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6223 hom., cov: 31)
  • Exomes 𝑓: 0.31 (65336 hom.)
• Consequence: VAMP1 ENST00000538970.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-6464690-G-T is Benign according to our data. Variant chr12-6464690-G-T is described in ClinVar as [Benign]. Clinvar id is 1253373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAMP1	NM_014231.5	c.340+200C>A		intron_variant	Intron 4 of 4	ENST00000396308.4	NP_055046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAMP1	ENST00000396308.4	c.340+200C>A		intron_variant	Intron 4 of 4	2	NM_014231.5	ENSP00000379602.3

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42605 AN: 151788 Hom.: 6221 Cov.: 31

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.311 AC: 416931 AN: 1339982 Hom.: 65336 Cov.: 34 AF XY: 0.312 AC XY: 204969 AN XY: 655962

African (AFR) AF: 0.203 AC: 5994 AN: 29496

American (AMR) AF: 0.185 AC: 4430 AN: 23976

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 5786 AN: 19452

East Asian (EAS) AF: 0.345 AC: 12940 AN: 37488

South Asian (SAS) AF: 0.346 AC: 23314 AN: 67478

European-Finnish (FIN) AF: 0.325 AC: 14032 AN: 43132

Middle Eastern (MID) AF: 0.330 AC: 1273 AN: 3852

European-Non Finnish (NFE) AF: 0.314 AC: 332310 AN: 1059708

Other (OTH) AF: 0.304 AC: 16852 AN: 55400

GnomAD4 genome AF: 0.281 AC: 42635 AN: 151906 Hom.: 6223 Cov.: 31 AF XY: 0.282 AC XY: 20960 AN XY: 74222

African (AFR) AF: 0.209 AC: 8644 AN: 41424

American (AMR) AF: 0.240 AC: 3668 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3472

East Asian (EAS) AF: 0.334 AC: 1715 AN: 5134

South Asian (SAS) AF: 0.353 AC: 1701 AN: 4814

European-Finnish (FIN) AF: 0.338 AC: 3566 AN: 10556

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21240 AN: 67908

Other (OTH) AF: 0.275 AC: 580 AN: 2108

Alfa AF: 0.297 Hom.: 24132

Bravo AF: 0.267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.53
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1034969; hg19: chr12-6573856; COSMIC: COSV56947052; COSMIC: COSV56947052;