rs61750615

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. BS1BP5PP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.6187C>T is a missense variant that replaces proline with serine at position 2063. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.04661 (based on 4353/91066 alleles in the South Asian population, with 145 homozygotes), which is higher than the ClinGen VWD VCEP BS1 threshold of >0.01 (BS1). At least 1 proband harboring the variant in the homozygous state exhibits a history of severe bleeding and a quantitative defect in VWF, consistent with VWD Type 3 (PMID:23354996), however, it is not yet clear whether this phenotype is sufficiently specific to meet PP4. While this variant is also reported to be present in the homozygous state in multiple other affected probands (PMID:23354996), PS4 cannot be considered because BS1 is met. The recombinant p.Pro2063Ser variant in COS-7 cells matches properties of the wild-type recombinant protein, including normal expression, secretion, and multimer formation, inconsistent with a quantitative defect relevant to VWD Type 3 (PMID:19566550). BS3_Supporting is not met because this criterion is considered not applicable to this gene-disease relationship. This variant has been observed in affected cases with an alternate molecular basis for disease, including in VWD Type 3 in cis with either the NM_000552.5(VWF):c.970C>T (p.Arg324Ter) variant (PMID:33550700) or the NM_000552.5(VWF):c.5200C>T (p.Gln1734Ter) variant (PMID:23702511). Both comparison variants have been classified as Pathogenic by the ClinGen VWD VCEP. Three other reported cases with diverse VWD diagnoses harbor this variant as well as a second variant in VWF (PMID:19404524, PMID:21534937, PMID:16985174), however, the comparison variants have not yet been classified by the ClinGen VWD VCEP. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, PP4. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA202650/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.0075 ( 16 hom., cov: 31)

Exomes 𝑓: 0.010 ( 192 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:13O:1

Conservation

PhyloP100: 8.27

Publications

35 publications found

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 Gene-Disease associations (from GenCC):

hereditary von Willebrand disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
von Willebrand disease type 2B
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
von Willebrand disease 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
von Willebrand disease 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
von Willebrand disease type 2A
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease type 2M
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
von Willebrand disease type 2N
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VWF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP4

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 rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.6187C>T	p.Pro2063Ser	missense_variant	Exon 36 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.6187C>T	p.Pro2063Ser	missense_variant	Exon 36 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.6187C>T	p.Pro2063Ser	missense_variant	Exon 36 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-550C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.00748

AC:

1139

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0425

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00801

Gnomad OTH

AF:

0.00911

GnomAD2 exomes

AF:

0.0126

AC:

3178

AN:

251442

AF XY:

0.0149

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0246

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00825

Gnomad OTH exome

AF:

0.0165

GnomAD4 exome

AF:

0.0103

AC:

15042

AN:

1461852

Hom.:

192

Cov.:

AF XY:

0.0118

AC XY:

8580

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.0111

AC:

495

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0243

AC:

635

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0481

AC:

4148

AN:

86250

European-Finnish (FIN)

AF:

0.00125

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0260

AC:

150

AN:

5768

European-Non Finnish (NFE)

AF:

0.00792

AC:

8806

AN:

1111984

Other (OTH)

AF:

0.0116

AC:

701

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

915

1830

2746

3661

4576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00747

AC:

1137

AN:

152290

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

579

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41566

American (AMR)

AF:

0.0125

AC:

192

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0426

AC:

205

AN:

4816

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00801

AC:

545

AN:

68016

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00871

Hom.:

Bravo

AF:

0.00741

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.0127

AC:

1545

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0111

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VWF: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Academic Unit of Haematology, University of Sheffield

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Hereditary von Willebrand disease

Uncertain:1Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2019

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000552.5(VWF):c.6187C>T is a missense variant that replaces proline with serine at position 2063. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.04661 (based on 4353/91066 alleles in the South Asian population, with 145 homozygotes), which is higher than the ClinGen VWD VCEP BS1 threshold of >0.01 (BS1). At least 1 proband harboring the variant in the homozygous state exhibits a history of severe bleeding and a quantitative defect in VWF, consistent with VWD Type 3 (PMID: 23354996), however, it is not yet clear whether this phenotype is sufficiently specific to meet PP4. While this variant is also reported to be present in the homozygous state in multiple other affected probands (PMID: 23354996), PS4 cannot be considered because BS1 is met. The recombinant p.Pro2063Ser variant in COS-7 cells matches properties of the wild-type recombinant protein, including normal expression, secretion, and multimer formation, inconsistent with a quantitative defect relevant to VWD Type 3 (PMID: 19566550). BS3_Supporting is not met because this criterion is considered not applicable to this gene-disease relationship. This variant has been observed in affected cases with an alternate molecular basis for disease, including in VWD Type 3 in cis with either the NM_000552.5(VWF):c.970C>T (p.Arg324Ter) variant (PMID: 33550700) or the NM_000552.5(VWF):c.5200C>T (p.Gln1734Ter) variant (PMID: 23702511). Both comparison variants have been classified as Pathogenic by the ClinGen VWD VCEP. Three other reported cases with diverse VWD diagnoses harbor this variant as well as a second variant in VWF (PMID: 19404524, PMID: 21534937, PMID: 16985174), however, the comparison variants have not yet been classified by the ClinGen VWD VCEP. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP5, PP4. (VCEP Rule specifications for von Willebrand disease type 2A, 2B and 2M v1.0.0; date of approval 08/13/2024) -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 17, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

von Willebrand disease type 1

Benign:2

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0080

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.7

PhyloP100

8.3

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.44

Sift

Uncertain

0.027

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.30

MPC

0.92

ClinPred

0.0098

GERP RS

4.9

Varity_R

0.27

gMVP

0.85

Mutation Taster

=28/72

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over