12-6110515-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.391G>A is a missense variant in VWF that replaces glycine with serine at position 131. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02093 (based on 1636/75004 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). This variant has been reported in the heterozygous state in at least 5 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. The computational predictor REVEL gives a score of 0.141, 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. 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, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6403810/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.0061 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 13 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: 4.97

Publications

6 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 -5 ACMG points.

BP4

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.391G>A	p.Gly131Ser	missense_variant	Exon 5 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.391G>A	p.Gly131Ser	missense_variant	Exon 5 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
VWF	ENST00000261405.10 link	c.391G>A	p.Gly131Ser	missense_variant	Exon 5 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000321023.5 link	n.*450G>A		non_coding_transcript_exon_variant	Exon 6 of 7	1		ENSP00000461331.1
VWF	ENST00000321023.5 link	n.*450G>A		3_prime_UTR_variant	Exon 6 of 7	1		ENSP00000461331.1
VWF	ENST00000538635.5 link	n.420G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	4

Frequencies

GnomAD3 genomes

AF:

0.00603

AC:

918

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00187

AC:

470

AN:

251492

AF XY:

0.00148

show subpopulations

Gnomad AFR exome

AF:

0.0215

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000971

AC:

1419

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

657

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0237

AC:

794

AN:

33480

American (AMR)

AF:

0.00192

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000278

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00815

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000309

AC:

344

AN:

1112012

Other (OTH)

AF:

0.00204

AC:

123

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

180

270

360

450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00606

AC:

922

AN:

152248

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

413

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0203

AC:

842

AN:

41524

American (AMR)

AF:

0.00327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68016

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00257

Hom.:

Bravo

AF:

0.00656

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00211

AC:

256

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VWF: BP4, BS1, BS2 -

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jul 20, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary von Willebrand disease

Uncertain:1Benign: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.391G>A is a missense variant in VWF that replaces glycine with serine at position 131. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02093 (based on 1636/75004 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). This variant has been reported in the heterozygous state in at least 5 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. The computational predictor REVEL gives a score of 0.141, 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. 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, BP4. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

von Willebrand disease type 1

Benign:1

Nov 07, 2019

Genetics and Molecular Pathology, SA Pathology

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

0.051

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.21

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.5

PhyloP100

5.0

PrimateAI

Benign

0.32

PROVEAN

Benign

2.3

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.095

Vest4

0.11

MVP

0.40

MPC

0.19

ClinPred

0.0096

GERP RS

4.7

Varity_R

0.033

gMVP

0.34

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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