12-6464583-C-T

Variant names:

• chr12-6464583-C-T
• rs2534717
• ENST00000538970.5:n.566G>A

Variant summary

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

The ENST00000538970.5(VAMP1):​n.566G>A variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,461,168 control chromosomes in the GnomAD database, including 70,288 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6221 hom., cov: 31)
  • Exomes 𝑓: 0.31 (64067 hom.)
• Consequence: VAMP1 ENST00000538970.5 splice_region, non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.827
• Publications: 25 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=-0.82).
• BP6: Variant 12-6464583-C-T is Benign according to our data. Variant chr12-6464583-C-T is described in ClinVar as [Benign]. Clinvar id is 1258404.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 rank	MANE	Protein	UniProt
VAMP1	NM_014231.5	c.341-97G>A		intron_variant	Intron 4 of 4	ENST00000396308.4	NP_055046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAMP1	ENST00000396308.4	c.341-97G>A		intron_variant	Intron 4 of 4	2	NM_014231.5	ENSP00000379602.3

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42627 AN: 151880 Hom.: 6219 Cov.: 31

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.271

GnomAD4 exome AF: 0.312 AC: 408057 AN: 1309170 Hom.: 64067 Cov.: 36 AF XY: 0.313 AC XY: 199075 AN XY: 636494

African (AFR) AF: 0.203 AC: 5772 AN: 28408

American (AMR) AF: 0.197 AC: 4024 AN: 20414

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 5692 AN: 19074

East Asian (EAS) AF: 0.345 AC: 12121 AN: 35096

South Asian (SAS) AF: 0.346 AC: 21877 AN: 63142

European-Finnish (FIN) AF: 0.328 AC: 14873 AN: 45382

Middle Eastern (MID) AF: 0.333 AC: 1528 AN: 4592

European-Non Finnish (NFE) AF: 0.314 AC: 325756 AN: 1039058

Other (OTH) AF: 0.304 AC: 16414 AN: 54004

GnomAD4 genome AF: 0.281 AC: 42657 AN: 151998 Hom.: 6221 Cov.: 31 AF XY: 0.282 AC XY: 20970 AN XY: 74292

African (AFR) AF: 0.209 AC: 8647 AN: 41442

American (AMR) AF: 0.240 AC: 3665 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1029 AN: 3468

East Asian (EAS) AF: 0.334 AC: 1718 AN: 5150

South Asian (SAS) AF: 0.353 AC: 1699 AN: 4818

European-Finnish (FIN) AF: 0.336 AC: 3560 AN: 10580

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21268 AN: 67944

Other (OTH) AF: 0.274 AC: 579 AN: 2112

Alfa AF: 0.296 Hom.: 9190

Bravo AF: 0.267

Asia WGS AF: 0.264 AC: 917 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	-0.82
CADD	Benign	6.3
DANN	Benign	0.56
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2534717; hg19: chr12-6573749;