12-6464690-G-T

Position:

• chr12-6464690-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361716.8(VAMP1):​c.*186C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 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 ENST00000361716.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148

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 -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/exons	MANE	UniProt
VAMP1	NM_014231.5	c.340+200C>A		intron_variant		ENST00000396308.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP1	ENST00000396308.4	c.340+200C>A		intron_variant		2	NM_014231.5	P1

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

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.346

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.314

Gnomad4 OTH exome AF: 0.304

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

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.338

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.275

Alfa AF: 0.300 Hom.: 11071

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

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