12-6462882-A-G

Variant names:

• chr12-6462882-A-G
• rs1045452
• NM_014231.5:c.*1588T>C

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.*1588T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,595,188 control chromosomes in the GnomAD database, including 402,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37884 hom., cov: 33)
  • Exomes 𝑓: 0.71 (364987 hom.)
• Consequence: VAMP1 NM_014231.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0740
• Publications: 30 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=-0.69).
• BP6: Variant 12-6462882-A-G is Benign according to our data. Variant chr12-6462882-A-G is described in ClinVar as [Benign]. Clinvar id is 1234868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAMP1	NM_014231.5	c.*1588T>C		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.*1588T>C		3_prime_UTR_variant	Exon 5 of 5	2	NM_014231.5	ENSP00000379602.3

Frequencies

GnomAD3 genomes AF: 0.704 AC: 107072 AN: 152040 Hom.: 37845 Cov.: 33

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.692 AC: 151463 AN: 219004 AF XY: 0.697

Gnomad AFR exome AF: 0.710

Gnomad AMR exome AF: 0.587

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.708

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.668

GnomAD4 exome AF: 0.710 AC: 1024573 AN: 1443030 Hom.: 364987 Cov.: 81 AF XY: 0.711 AC XY: 509193 AN XY: 715800

African (AFR) AF: 0.715 AC: 23705 AN: 33152

American (AMR) AF: 0.593 AC: 24698 AN: 41680

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 14720 AN: 25762

East Asian (EAS) AF: 0.784 AC: 30527 AN: 38938

South Asian (SAS) AF: 0.786 AC: 65303 AN: 83100

European-Finnish (FIN) AF: 0.707 AC: 36992 AN: 52350

Middle Eastern (MID) AF: 0.584 AC: 3350 AN: 5736

European-Non Finnish (NFE) AF: 0.711 AC: 783725 AN: 1102562

Other (OTH) AF: 0.695 AC: 41553 AN: 59750

GnomAD4 genome AF: 0.704 AC: 107161 AN: 152158 Hom.: 37884 Cov.: 33 AF XY: 0.704 AC XY: 52387 AN XY: 74382

African (AFR) AF: 0.720 AC: 29861 AN: 41500

American (AMR) AF: 0.652 AC: 9968 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1991 AN: 3472

East Asian (EAS) AF: 0.777 AC: 4011 AN: 5164

South Asian (SAS) AF: 0.788 AC: 3808 AN: 4830

European-Finnish (FIN) AF: 0.707 AC: 7481 AN: 10588

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47878 AN: 67992

Other (OTH) AF: 0.660 AC: 1395 AN: 2114

Alfa AF: 0.686 Hom.: 48032

Bravo AF: 0.694

Asia WGS AF: 0.761 AC: 2644 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Spastic ataxia 1 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myasthenic syndrome, congenital, 25, presynaptic Benign:1

Dec 05, 2021

Genome-Nilou Lab

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	-0.69
CADD	Benign	8.3
DANN	Benign	0.72
PhyloP100		0.074
Mutation Taster		=47/53	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1045452; hg19: chr12-6572048; COSMIC: COSV56947017; COSMIC: COSV56947017;