12-6029409-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS1PP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.2900G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 967. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02526 (based on 967/75012 alleles in the African / African-American population, with 34 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in at least 1 patient with a diagnosis of VWD Type 3 and a phenotype including reduced quantity of VWF antigen. However, PP4 was not met due to the absence of other phenotype details and the presence of two additional variants (p.C350AfsX107 and p.C2774W) without reported confirmation of phase (PMID:23777763). This variant has also been reported in the heterozygous state in at least 7 reported healthy control individuals with no bleeding history and normal lab values (PMID:22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402913/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.0077 ( 18 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 17 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:9

Conservation

PhyloP100: 5.69

Publications

5 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 -3 ACMG points.

PP4

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.2900G>A	p.Gly967Asp	missense_variant	Exon 22 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2900G>A	p.Gly967Asp	missense_variant	Exon 22 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2900G>A	p.Gly967Asp	missense_variant	Exon 22 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-35475G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.00766

AC:

1166

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00192

AC:

483

AN:

251372

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.0257

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000749

AC:

1095

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000622

AC XY:

452

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0260

AC:

872

AN:

33480

American (AMR)

AF:

0.00192

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1112012

Other (OTH)

AF:

0.00190

AC:

115

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00767

AC:

1167

AN:

152250

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

560

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0264

AC:

1095

AN:

41532

American (AMR)

AF:

0.00359

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00278

Hom.:

Bravo

AF:

0.00903

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0247

AC:

109

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00242

AC:

294

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:4

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 25, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely 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

- -

Apr 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22197721, 28971901, 23777763) -

May 16, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 15, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: VWF c.2900G>A (p.Gly967Asp) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 282840 control chromosomes, predominantly at a frequency of 0.026 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database strongly suggests that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2900G>A has been reported in the literature in multiple individuals affected with clinical features of Von Willebrand Disease (e.g., Sadler_2021, Borras_2017, Ornaghi_2021), however, these reports do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. c.2900G>A has also been reported in the literature in healthy control populations (e.g., Bellissimo_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22197721, 28971901, 33550700, 33556167). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign or likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Aug 12, 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:c.2900G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 967. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02526 (based on 967/75012 alleles in the African / African-American population, with 34 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in at least 1 patient with a diagnosis of VWD Type 3 and a phenotype including reduced quantity of VWF antigen. However, PP4 was not met due to the absence of other phenotype details and the presence of two additional variants (p.C350AfsX107 and p.C2774W) without reported confirmation of phase (PMID:23777763). This variant has also been reported in the heterozygous state in at least 7 reported healthy control individuals with no bleeding history and normal lab values (PMID: 22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, PP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.58

PhyloP100

5.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.31

Sift

Uncertain

0.025

Sift4G

Uncertain

0.0080

Polyphen

0.96

Vest4

0.64

MVP

0.82

MPC

0.86

ClinPred

0.035

GERP RS

3.7

Varity_R

0.33

gMVP

0.88

Mutation Taster

=6/94

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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