rs71584837

Variant names:

• chr12-6462840-G-A
• rs71584837
• ENST00000400911.7:c.343C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016830.4(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. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (19 hom.)
• Consequence: VAMP1 NM_016830.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.347
• Publications: 6 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 (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 Benign/Likely_benign. ClinVar VariationId is 448851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016830.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP1	NM_014231.5	MANE Select	c.*1630C>T		3_prime_UTR	Exon 5 of 5	NP_055046.1	P23763-1
	VAMP1	NM_016830.4		c.343C>T	p.Arg115Trp	missense splice_region	Exon 5 of 5	NP_058439.1	P23763-2
	VAMP1	NM_199245.3		c.*2036C>T		3_prime_UTR	Exon 4 of 4	NP_954740.1	P23763-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VAMP1	ENST00000400911.7	TSL:1	c.343C>T	p.Arg115Trp	missense splice_region	Exon 5 of 5	ENSP00000383702.3	P23763-2
	VAMP1	ENST00000396308.4	TSL:2 MANE Select	c.*1630C>T		3_prime_UTR	Exon 5 of 5	ENSP00000379602.3	P23763-1
	VAMP1	ENST00000361716.8	TSL:1	c.*2036C>T		3_prime_UTR	Exon 4 of 4	ENSP00000355122.3	P23763-3

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

GnomAD2 exomes AF: 0.00331 AC: 778 AN: 234946 AF XY: 0.00347

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 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

African (AFR) AF: 0.000839 AC: 28 AN: 33364

American (AMR) AF: 0.00179 AC: 78 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 26 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00205 AC: 173 AN: 84510

European-Finnish (FIN) AF: 0.00538 AC: 285 AN: 52992

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5754

European-Non Finnish (NFE) AF: 0.00518 AC: 5741 AN: 1108200

Other (OTH) AF: 0.00339 AC: 204 AN: 60116

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

African (AFR) AF: 0.000962 AC: 40 AN: 41566

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00598 AC: 407 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00441 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
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
PhyloP100		0.35
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
Mutation Taster		=95/5	polymorphism

Splicing

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

Other links and lift over

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