12-6463025-T-C

Variant names:

• chr12-6463025-T-C
• rs12964
• NM_014231.5:c.*1445A>G

Variant summary

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

The NM_014231.5(VAMP1):​c.*1445A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,546,508 control chromosomes in the GnomAD database, including 194,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17267 hom., cov: 32)
  • Exomes 𝑓: 0.50 (177204 hom.)
• Consequence: VAMP1 NM_014231.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 31 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=-0.79).
• BP6: Variant 12-6463025-T-C is Benign according to our data. Variant chr12-6463025-T-C is described in ClinVar as [Benign]. Clinvar id is 1253157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAMP1	NM_014231.5	c.*1445A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000396308.4	NP_055046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAMP1	ENST00000396308.4	c.*1445A>G		3_prime_UTR_variant	Exon 5 of 5	2	NM_014231.5	ENSP00000379602.3

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71256 AN: 151934 Hom.: 17257 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.766

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.501 AC: 698415 AN: 1394456 Hom.: 177204 Cov.: 72 AF XY: 0.502 AC XY: 345213 AN XY: 687744

African (AFR) AF: 0.352 AC: 11109 AN: 31580

American (AMR) AF: 0.415 AC: 14818 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 11137 AN: 25174

East Asian (EAS) AF: 0.780 AC: 27868 AN: 35738

South Asian (SAS) AF: 0.556 AC: 44043 AN: 79200

European-Finnish (FIN) AF: 0.512 AC: 22980 AN: 44888

Middle Eastern (MID) AF: 0.442 AC: 2367 AN: 5350

European-Non Finnish (NFE) AF: 0.496 AC: 535115 AN: 1078888

Other (OTH) AF: 0.500 AC: 28978 AN: 57944

GnomAD4 genome AF: 0.469 AC: 71307 AN: 152052 Hom.: 17267 Cov.: 32 AF XY: 0.473 AC XY: 35160 AN XY: 74304

African (AFR) AF: 0.364 AC: 15092 AN: 41484

American (AMR) AF: 0.474 AC: 7237 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1538 AN: 3468

East Asian (EAS) AF: 0.766 AC: 3952 AN: 5160

South Asian (SAS) AF: 0.573 AC: 2769 AN: 4830

European-Finnish (FIN) AF: 0.519 AC: 5483 AN: 10568

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.494 AC: 33556 AN: 67966

Other (OTH) AF: 0.475 AC: 1003 AN: 2110

Alfa AF: 0.483 Hom.: 55917

Bravo AF: 0.457

Asia WGS AF: 0.626 AC: 2174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.6
DANN	Benign	0.78
PhyloP100		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12964; hg19: chr12-6572191; COSMIC: COSV56945780; COSMIC: COSV56945780;