2-98119762-C-T

Position:

• chr2-98119762-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_144992.5(VWA3B):​c.541C>T​(p.Arg181Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0781 in 1,612,976 control chromosomes in the GnomAD database, including 6,040 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1236 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4804 hom.)
• Consequence: VWA3B NM_144992.5 missense, splice_region
• Scores: Splicing: ADA: 0.00001587
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.336

Genes affected

VWA3B (HGNC:28385): (von Willebrand factor A domain containing 3B) This gene encodes an intracellular protein that contains a von Willebrand factor type A domain. Intracellular proteins with VWA domains are thought to function in transcription, DNA repair, ribosomal and membrane transport and the proteasome. Mutations in this gene are associated with Spinocerebellar ataxia, autosomal recessive 22. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2017]

VWA3B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004476458).
• BP6: Variant 2-98119762-C-T is Benign according to our data. Variant chr2-98119762-C-T is described in ClinVar as [Benign]. Clinvar id is 3059897.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWA3B	NM_144992.5	c.541C>T	p.Arg181Trp	missense_variant, splice_region_variant	4/28	ENST00000477737.6	NP_659429.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA3B	ENST00000477737.6	c.541C>T	p.Arg181Trp	missense_variant, splice_region_variant	4/28	1	NM_144992.5	ENSP00000417955.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16904 AN: 151922 Hom.: 1234 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.0678

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0804

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0708

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.0796 AC: 19769 AN: 248206 Hom.: 1033 AF XY: 0.0782 AC XY: 10536 AN XY: 134694

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.0387

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.0767

Gnomad FIN exome AF: 0.0413

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0724

GnomAD4 exome AF: 0.0746 AC: 109041 AN: 1460936 Hom.: 4804 Cov.: 32 AF XY: 0.0748 AC XY: 54331 AN XY: 726596

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.0424

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.0768

Gnomad4 FIN exome AF: 0.0424

Gnomad4 NFE exome AF: 0.0687

Gnomad4 OTH exome AF: 0.0826

GnomAD4 genome AF: 0.111 AC: 16911 AN: 152040 Hom.: 1236 Cov.: 32 AF XY: 0.110 AC XY: 8138 AN XY: 74316

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0676

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.0811

Gnomad4 FIN AF: 0.0397

Gnomad4 NFE AF: 0.0708

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0815 Hom.: 1481

Bravo AF: 0.116

TwinsUK AF: 0.0736 AC: 273

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.195 AC: 742

ESP6500EA AF: 0.0729 AC: 602

ExAC AF: 0.0835 AC: 10086

Asia WGS AF: 0.126 AC: 437 AN: 3478

EpiCase AF: 0.0791

EpiControl AF: 0.0739

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

VWA3B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.28	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.063
Sift	Benign	0.059	T
Sift4G	Benign	0.068	T
Polyphen		0.096	B
Vest4		0.067
MPC		0.092
ClinPred		0.033	T
GERP RS		-2.8
Varity_R		0.076
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.032
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

LitVar

Other links and lift over

dbSNP: rs2305355; hg19: chr2-98736225; COSMIC: COSV68245107; COSMIC: COSV68245107;