12-6462882-A-G

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 0.0740

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=-0.69).
• 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/exons	MANE	UniProt
VAMP1	NM_014231.5	c.*1588T>C		3_prime_UTR_variant	5/5	ENST00000396308.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP1	ENST00000396308.4	c.*1588T>C		3_prime_UTR_variant	5/5	2	NM_014231.5	P1

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

GnomAD3 exomes AF: 0.692 AC: 151463 AN: 219004 Hom.: 52706 AF XY: 0.697 AC XY: 82255 AN XY: 118068

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 SAS exome AF: 0.789

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

Gnomad4 AFR exome AF: 0.715

Gnomad4 AMR exome AF: 0.593

Gnomad4 ASJ exome AF: 0.571

Gnomad4 EAS exome AF: 0.784

Gnomad4 SAS exome AF: 0.786

Gnomad4 FIN exome AF: 0.707

Gnomad4 NFE exome AF: 0.711

Gnomad4 OTH exome AF: 0.695

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

Gnomad4 AFR AF: 0.720

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.788

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.660

Alfa AF: 0.686 Hom.: 36929

Bravo AF: 0.694

Asia WGS AF: 0.761 AC: 2644 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic ataxia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Myasthenic syndrome, congenital, 25, presynaptic Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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	-0.69
Cadd	Benign	8.3
Dann	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

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