rs7962217

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg) variant in VWF is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 2705. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1227 (based on 11352/91062 alleles in the South Asian population, including 829 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. As reported in PMID:26105150 the variant is significantly associated with lower plasma levels of FVIII but not vWF. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6401404/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.045 ( 204 hom., cov: 32)

Exomes 𝑓: 0.059 ( 3022 hom. )

Consequence

VWF
NM_000552.5 missense, splice_region

Scores

Splicing: ADA: 0.9526

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 5.94

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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	Exon 49 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	Exon 49 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	Exon 49 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000612016.1 link	n.522G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5
VWF	ENST00000621700.1 link	n.431G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0448

AC:

6807

AN:

152098

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.0612

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0449

GnomAD3 exomes

AF:

0.0593

AC:

14897

AN:

251422

Hom.:

627

AF XY:

0.0641

AC XY:

8712

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.0702

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.00321

Gnomad SAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.0595

Gnomad NFE exome

AF:

0.0558

Gnomad OTH exome

AF:

0.0518

GnomAD4 exome

AF:

0.0591

AC:

86371

AN:

1461538

Hom.:

3022

Cov.:

AF XY:

0.0611

AC XY:

44423

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.0162

Gnomad4 AMR exome

AF:

0.0654

Gnomad4 ASJ exome

AF:

0.0333

Gnomad4 EAS exome

AF:

0.00202

Gnomad4 SAS exome

AF:

0.125

Gnomad4 FIN exome

AF:

0.0591

Gnomad4 NFE exome

AF:

0.0577

Gnomad4 OTH exome

AF:

0.0580

GnomAD4 genome

AF:

0.0447

AC:

6798

AN:

152216

Hom.:

204

Cov.:

AF XY:

0.0448

AC XY:

3332

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0176

Gnomad4 AMR

AF:

0.0432

Gnomad4 ASJ

AF:

0.0360

Gnomad4 EAS

AF:

0.00289

Gnomad4 SAS

AF:

0.119

Gnomad4 FIN

AF:

0.0612

Gnomad4 NFE

AF:

0.0568

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0522

Hom.:

488

Bravo

AF:

0.0414

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0602

AC:

232

ESP6500AA

AF:

0.0197

AC:

ESP6500EA

AF:

0.0578

AC:

497

ExAC

AF:

0.0593

AC:

7197

Asia WGS

AF:

0.0530

AC:

186

AN:

3478

EpiCase

AF:

0.0601

EpiControl

AF:

0.0566

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease

Benign:2

Aug 13, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg) variant in VWF is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 2705. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1227 (based on 11352/91062 alleles in the South Asian population, including 829 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. As reported in PMID: 26105150 the variant is significantly associated with lower plasma levels of FVIII but not vWF. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1 -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.1

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.30

MutPred

0.39

Gain of catalytic residue at L2702 (P = 0.0017);

MPC

1.0

ClinPred

0.024

GERP RS

5.5

Varity_R

0.53

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.79

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