12-6463025-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.00

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 Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
VAMP1	NM_014231.5	c.*1445A>G		3_prime_UTR_variant	5/5	ENST00000396308.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP1	ENST00000396308.4	c.*1445A>G		3_prime_UTR_variant	5/5	2	NM_014231.5	P1

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

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.442

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.556

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.766

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.475

Alfa AF: 0.488 Hom.: 23470

Bravo AF: 0.457

Asia WGS AF: 0.626 AC: 2174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.6
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

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

Publications

LitVar

Other links and lift over

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