Genetic Variant VAMP1:c.*326A>G (chr12-6464550-T-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_014231.5(VAMP1):c.341-64A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,465,846 control chromosomes in the GnomAD database, including 70,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6221 hom., cov: 31)

Exomes 𝑓: 0.31 ( 64305 hom. )

Consequence

VAMP1
NM_014231.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.14

Publications

15 publications found

Variant links:

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]

VAMP1 links:

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]

TAPBPL links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 12-6464550-T-C is Benign according to our data. Variant chr12-6464550-T-C is described in ClinVar as [Benign]. Clinvar id is 1295842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAMP1	NM_014231.5 link	c.341-64A>G		intron_variant	Intron 4 of 4	ENST00000396308.4	NP_055046.1	P23763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAMP1	ENST00000396308.4 link	c.341-64A>G		intron_variant	Intron 4 of 4	2	NM_014231.5	ENSP00000379602.3		P23763-1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42630

AN:

151520

Hom.:

6219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.335

Gnomad SAS

AF:

0.354

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.313

Gnomad OTH

AF:

0.273

GnomAD4 exome

AF:

0.312

AC:

409615

AN:

1314208

Hom.:

64305

Cov.:

AF XY:

0.313

AC XY:

200051

AN XY:

639518

show subpopulations

African (AFR)

AF:

0.203

AC:

5801

AN:

28542

American (AMR)

AF:

0.195

AC:

4121

AN:

21128

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

5747

AN:

19256

East Asian (EAS)

AF:

0.346

AC:

12155

AN:

35176

South Asian (SAS)

AF:

0.347

AC:

22097

AN:

63692

European-Finnish (FIN)

AF:

0.328

AC:

15035

AN:

45902

Middle Eastern (MID)

AF:

0.329

AC:

1692

AN:

5148

European-Non Finnish (NFE)

AF:

0.314

AC:

326448

AN:

1041118

Other (OTH)

AF:

0.305

AC:

16519

AN:

54246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

14797

29594

44390

59187

73984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.281

AC:

42660

AN:

151638

Hom.:

6221

Cov.:

AF XY:

0.283

AC XY:

20977

AN XY:

74080

show subpopulations

African (AFR)

AF:

0.209

AC:

8641

AN:

41276

American (AMR)

AF:

0.240

AC:

3668

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1029

AN:

3466

East Asian (EAS)

AF:

0.335

AC:

1721

AN:

5140

South Asian (SAS)

AF:

0.355

AC:

1702

AN:

4800

European-Finnish (FIN)

AF:

0.339

AC:

3562

AN:

10516

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.313

AC:

21264

AN:

67868

Other (OTH)

AF:

0.276

AC:

581

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1558

3117

4675

6234

7792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.293

Hom.:

5712

Bravo

AF:

0.267

Asia WGS

AF:

0.264

AC:

918

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.41

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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12-6464550-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over