rs1800380

chr12-6029429-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):c.2880G>A(p.Arg960=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,613,814 control chromosomes in the GnomAD database, including 49,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5042 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44836 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: -0.749

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-6029429-C-T is Benign according to our data. Variant chr12-6029429-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6029429-C-T is described in Lovd as [Benign]. Variant chr12-6029429-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.749 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2880G>A	p.Arg960=	synonymous_variant	22/52	ENST00000261405.10
VWF	XM_047429501.1	c.2880G>A	p.Arg960=	synonymous_variant	22/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2880G>A	p.Arg960=	synonymous_variant	22/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-35495G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37864 AN: 151868 Hom.: 5039 Cov.: 31

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.204 AC: 51204 AN: 251332 Hom.: 6195 AF XY: 0.201 AC XY: 27348 AN XY: 135846

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.117

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.240 AC: 350235 AN: 1461828 Hom.: 44836 Cov.: 38 AF XY: 0.236 AC XY: 171420 AN XY: 727218

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.251

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.249 AC: 37900 AN: 151986 Hom.: 5042 Cov.: 31 AF XY: 0.243 AC XY: 18035 AN XY: 74304

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.234

Alfa AF: 0.250 Hom.: 6462

Bravo AF: 0.250

Asia WGS AF: 0.0790 AC: 277 AN: 3478

EpiCase AF: 0.250

EpiControl AF: 0.255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 32.021% in gnomAD_Exomes) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.81
Dann	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs1800380; hg19: chr12-6138595; COSMIC: COSV54636428;