12-6462840-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000400911.7(VAMP1):c.343C>T(p.Arg115Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,606,292 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (19 hom.)
• Consequence: VAMP1 ENST00000400911.7 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.347

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 (MetaRNN=0.0025634766).
• BP6: Variant 12-6462840-G-A is Benign according to our data. Variant chr12-6462840-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6462840-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00373 (568/152316) while in subpopulation NFE AF= 0.00598 (407/68024). AF 95% confidence interval is 0.0055. There are 3 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VAMP1	NM_014231.5	c.*1630C>T		3_prime_UTR_variant	5/5	ENST00000396308.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VAMP1	ENST00000396308.4	c.*1630C>T		3_prime_UTR_variant	5/5	2	NM_014231.5	P1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152198 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00598

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00331 AC: 778 AN: 234946 Hom.: 3 AF XY: 0.00347 AC XY: 442 AN XY: 127222

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000821

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00192

Gnomad FIN exome AF: 0.00525

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00450 AC: 6545 AN: 1453976 Hom.: 19 Cov.: 29 AF XY: 0.00439 AC XY: 3170 AN XY: 722266

Gnomad4 AFR exome AF: 0.000839

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.00538

Gnomad4 NFE exome AF: 0.00518

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152316 Hom.: 3 Cov.: 33 AF XY: 0.00381 AC XY: 284 AN XY: 74480

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00594

Gnomad4 NFE AF: 0.00598

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00482 Hom.: 0

Bravo AF: 0.00323

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000766 AC: 3

ESP6500EA AF: 0.00530 AC: 44

ExAC AF: 0.00351 AC: 424

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	VAMP1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Uncertain	1.0
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	0.40	N
REVEL	Benign	0.041
Sift	Uncertain	0.0040	D
Polyphen		0.0	B
Vest4		0.10
MVP		0.043
ClinPred		0.021	T
GERP RS		1.5

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71584837; hg19: chr12-6572006; COSMIC: COSV56947683; COSMIC: COSV56947683;