12-6019004-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000552.5(VWF):c.4414G>C (p.Asp1472His) is common in the general population with Grpmax filtering allele frequency of 0.5033 in gnomAD v4.1 (based on 38011/74882 alleles in the African/African American population). This is above the threshold of >0.1 (BA1). The computational predictor REVEL gives a score of 0.188, 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 does not predict an impact to splicing with this variant. This variant does appear to impact laboratory values; the mean VWF:RCo/VWF:Ag ratio of 0.75-0.82 was significantly reduced compared to 0.91-0.97 for WT in 275 healthy adult individuals harboring the Asp1472His variant (PMID:20231421). In summary this variant meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402534/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.21 ( 5738 hom., cov: 31)

Exomes 𝑓: 0.10 ( 11370 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -0.121

Publications

65 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: Benign. The variant received -9 ACMG points.

BP4

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

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.4414G>C	p.Asp1472His	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.4414G>C	p.Asp1472His	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.4414G>C	p.Asp1472His	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5 link	n.421-25070G>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.208

AC:

31589

AN:

151844

Hom.:

5730

Cov.:

show subpopulations

Gnomad AFR

AF:

0.500

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.0576

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0903

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.119

AC:

29448

AN:

248378

AF XY:

0.116

show subpopulations

Gnomad AFR exome

AF:

0.509

Gnomad AMR exome

AF:

0.0733

Gnomad ASJ exome

AF:

0.0597

Gnomad EAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0768

Gnomad NFE exome

AF:

0.0886

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.104

AC:

152489

AN:

1461350

Hom.:

11370

Cov.:

AF XY:

0.104

AC XY:

75805

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.518

AC:

17322

AN:

33468

American (AMR)

AF:

0.0798

AC:

3565

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0582

AC:

1521

AN:

26118

East Asian (EAS)

AF:

0.108

AC:

4293

AN:

39682

South Asian (SAS)

AF:

0.146

AC:

12554

AN:

86194

European-Finnish (FIN)

AF:

0.0761

AC:

4063

AN:

53414

Middle Eastern (MID)

AF:

0.119

AC:

684

AN:

5758

European-Non Finnish (NFE)

AF:

0.0909

AC:

101083

AN:

1111674

Other (OTH)

AF:

0.123

AC:

7404

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

7211

14422

21632

28843

36054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3994

7988

11982

15976

19970

<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:

0.208

AC:

31629

AN:

151962

Hom.:

5738

Cov.:

AF XY:

0.205

AC XY:

15247

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.500

AC:

20689

AN:

41414

American (AMR)

AF:

0.127

AC:

1940

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0576

AC:

200

AN:

3470

East Asian (EAS)

AF:

0.115

AC:

592

AN:

5136

South Asian (SAS)

AF:

0.148

AC:

711

AN:

4806

European-Finnish (FIN)

AF:

0.0760

AC:

805

AN:

10590

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0903

AC:

6139

AN:

67956

Other (OTH)

AF:

0.205

AC:

432

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1020

2040

3059

4079

5099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.0764

Hom.:

238

Bravo

AF:

0.226

TwinsUK

AF:

0.0882

AC:

327

ALSPAC

AF:

0.0877

AC:

338

ESP6500AA

AF:

0.393

AC:

1717

ESP6500EA

AF:

0.0657

AC:

565

ExAC

AF:

0.129

AC:

15584

EpiCase

AF:

0.0910

EpiControl

AF:

0.0912

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

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

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary von Willebrand disease

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The missense variant NM_000552.5(VWF):c.4414G>C (p.Asp1472His) is common in the general population with Grpmax filtering allele frequency of 0.5033 in gnomAD v4.1 (based on 38011/74882 alleles in the African/African American population). This is above the threshold of >0.1 (BA1). The computational predictor REVEL gives a score of 0.188, 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 does not predict an impact to splicing with this variant. This variant does appear to impact laboratory values; the mean VWF:RCo/VWF:Ag ratio of 0.75-0.82 was significantly reduced compared to 0.91-0.97 for WT in 275 healthy adult individuals harboring the Asp1472His variant (PMID:20231421). In summary this variant meets criteria to be classified as benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD: BA1, BP4. -

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 2M

Benign:1

Aug 04, 2017

Versiti Diagnostic Laboratories, Versiti, Inc

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.4414G>C in exon 28 of the VWF gene changes aspartic acid at codon 1472 to histidine (p.D1472H). The p.D1472H variant is common in the general population (12%, Exome Aggregation Consortium) and frequently found in individuals of African descent (50%, Exome Aggregation Consortium). Although the p.D1472H variant is not thought to cause type 1 or 2M von Willebrand disease (Flood, 2010), individuals who are heterozygous or homozygous for p.D1472H may exhibit reduced ratio of VWF ristocetin cofactor activity to VWF antigen. However, p.D1472H does not have physiological consequences; specifically it does not affect VWF multimer distribution or ristocetin-independent binding of VWF to GP1b complex, and does not result in increased risk for bleeding. In summary, VWF c.4414G>C, p.D1472H, is a benign variant with respect to von Willebrand disease. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.083

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.27

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.55

MetaRNN

Benign

0.000024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

-0.12

PrimateAI

Benign

0.24

PROVEAN

Benign

0.18

REVEL

Benign

0.19

Sift

Benign

0.15

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.040

MPC

0.32

ClinPred

0.0065

GERP RS

0.81

Varity_R

0.032

gMVP

0.49

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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