rs1053523

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000552.5(VWF):c.6846A>G(p.Thr2282Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,996 control chromosomes in the GnomAD database, including 17,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1862 hom., cov: 33)

Exomes 𝑓: 0.14 ( 16055 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: -1.38

Variant links:

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]

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 12-5985618-T-C is Benign according to our data. Variant chr12-5985618-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5985618-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.6846A>G	p.Thr2282Thr	synonymous_variant	Exon 39 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.6846A>G	p.Thr2282Thr	synonymous_variant	Exon 39 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.6846A>G	p.Thr2282Thr	synonymous_variant	Exon 39 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22640

AN:

152134

Hom.:

1863

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0877

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0668

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.145

GnomAD3 exomes

AF:

0.117

AC:

29329

AN:

251008

Hom.:

2137

AF XY:

0.114

AC XY:

15521

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.0753

Gnomad ASJ exome

AF:

0.137

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0678

Gnomad FIN exome

AF:

0.107

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.141

AC:

206671

AN:

1461744

Hom.:

16055

Cov.:

AF XY:

0.139

AC XY:

101168

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.195

Gnomad4 AMR exome

AF:

0.0787

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0680

Gnomad4 FIN exome

AF:

0.108

Gnomad4 NFE exome

AF:

0.155

Gnomad4 OTH exome

AF:

0.134

GnomAD4 genome

AF:

0.149

AC:

22634

AN:

152252

Hom.:

1862

Cov.:

AF XY:

0.143

AC XY:

10679

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.131

Gnomad4 ASJ

AF:

0.134

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0668

Gnomad4 FIN

AF:

0.103

Gnomad4 NFE

AF:

0.151

Gnomad4 OTH

AF:

0.144

Alfa

AF:

0.152

Hom.:

848

Bravo

AF:

0.152

Asia WGS

AF:

0.0450

AC:

161

AN:

3478

EpiCase

AF:

0.149

EpiControl

AF:

0.153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 19.693% 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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

von Willebrand disease type 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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

-0.65

CADD

Benign

0.30

DANN

Benign

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over