rs61749367

Positions:

chr12-6019732-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP5BS1

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.3686T>G is a missense variant encoding a substitution of valine by glycine at position 1229. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID:8134377, PMID:17190853, PMID:31064749, PMID:16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID:8134377, PMID:2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least three control individuals (PMID:22197721). The computational predictor REVEL gives a score of 0.149, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID:16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01529 (based on 1200/74796 alleles, with 10 homozygotes) in the African/African-American population, which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228433/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.0064 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 11 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:5B:6O:1

Conservation

PhyloP100: 3.55

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:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

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

BP5

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.3686T>G	p.Val1229Gly	missense_variant	28/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.3686T>G	p.Val1229Gly	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.3686T>G	p.Val1229Gly	missense_variant	28/52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000539641.1 linkuse as main transcript	n.484T>G		non_coding_transcript_exon_variant	3/3	3
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25798T>G		intron_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00638

AC:

971

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00157

AC:

380

AN:

241848

Hom.:

AF XY:

0.00158

AC XY:

208

AN XY:

131946

show subpopulations

Gnomad AFR exome

AF:

0.00983

Gnomad AMR exome

AF:

0.000702

Gnomad ASJ exome

AF:

0.000303

Gnomad EAS exome

AF:

0.00115

Gnomad SAS exome

AF:

0.00298

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000855

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.00180

AC:

2626

AN:

1458030

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1421

AN XY:

725198

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.00108

Gnomad4 ASJ exome

AF:

0.000307

Gnomad4 EAS exome

AF:

0.000731

Gnomad4 SAS exome

AF:

0.00515

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.00317

GnomAD4 genome

AF:

0.00641

AC:

977

AN:

152324

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00871

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00187

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00571

Hom.:

Bravo

AF:

0.00703

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00204

AC:

247

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 30, 2020	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2021	See Variant Classification Assertion Criteria. -

Hereditary von Willebrand disease

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely benign, reviewed by expert panel	curation	ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	Aug 12, 2024	NM_000552.5(VWF):c.3686T>G is a missense variant encoding a substitution of valine by glycine at position 1229. It has been reported in at least seven probands, two of whom have a phenotype specific for VWD Type 2B and one of whom has a phenotype specific for VWD Type 2M (PMID: 8134377, PMID: 17190853, PMID: 31064749, PMID: 16115133). However, the phenotypes are not consistent, and other variants present in cis or in trans are suspected to be disease-causing. At least one patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotypes of loss of high molecular weight multimers and increased ristocetin-induced platelet aggregation showing gain of function, which together are highly specific for VWD type 2B (PMID: 8134377, PMID: 2657729). Although three other genotype-positive family members were similarly affected with a VWD Type 2B phenotype, the patients harbored other variants in cis, including p.Arg1306Trp, which has been classified as Pathogenic by the ClinGen VWD VCEP (BP5). The variant has also been observed in at least three control individuals (PMID: 22197721). The computational predictor REVEL gives a score of 0.149, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. RIPA studies indicate that this variant does not contribute to enhanced ristocetin-induced platelet aggregation and that another variant found in the same patient was responsible instead (PMID: 16115133). The Grpmax filtering allele frequency in gnomAD v4.1 is 0.01529 (based on 1200/74796 alleles, with 10 homozygotes) in the African/African-American population, which is above the ClinGen VWD VCEP threshold (>0.01) for BS1. In summary, the variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, BP4. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 03, 2018	- -

von Willebrand disease type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Apr 21, 2021

- -

Abnormality of coagulation

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

von Willebrand disease type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Apr 21, 2021

- -

von Willebrand disease type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Apr 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.35

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.020

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-3.0

PrimateAI

Benign

0.34

PROVEAN

Benign

2.4

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.21

MVP

0.37

MPC

0.35

ClinPred

0.0028

GERP RS

4.9

Varity_R

0.20

gMVP

0.81

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