rs566672558

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BA1

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.3485C>T is a missense variant that replaces proline with leucine at position 1162. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.2036 (based on 7087/34136 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). Heterologous expression of the variant protein revealed similarities to the wild-type VWF control in secretion, collagen binding, GPIb binding, and multimerization (PMID:28544236). The computational predictor REVEL gives a score of 0.677, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402756/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.054 ( 530 hom., cov: 11)

Exomes 𝑓: 0.0082 ( 275 hom. )

Failed GnomAD Quality Control

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: 6.35

Publications

3 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 -7 ACMG points.

PP3

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.3485C>T	p.Pro1162Leu	missense_variant	Exon 26 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.3485C>T	p.Pro1162Leu	missense_variant	Exon 26 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.3485C>T	p.Pro1162Leu	missense_variant	Exon 26 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5 link	n.421-28859C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0539

AC:

4858

AN:

90098

Hom.:

528

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0302

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000805

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0182

Gnomad NFE

AF:

0.000973

Gnomad OTH

AF:

0.0644

GnomAD2 exomes

AF:

0.0256

AC:

1391

AN:

54328

AF XY:

0.0228

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.0179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.00989

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00824

AC:

3629

AN:

440470

Hom.:

275

Cov.:

AF XY:

0.00701

AC XY:

1628

AN XY:

232400

show subpopulations

African (AFR)

AF:

0.209

AC:

2567

AN:

12308

American (AMR)

AF:

0.0184

AC:

347

AN:

18854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13506

East Asian (EAS)

AF:

0.000101

AC:

AN:

29826

South Asian (SAS)

AF:

0.000489

AC:

AN:

45028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27572

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

1926

European-Non Finnish (NFE)

AF:

0.000899

AC:

239

AN:

265960

Other (OTH)

AF:

0.0165

AC:

420

AN:

25490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

157

315

472

630

787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0540

AC:

4870

AN:

90138

Hom.:

530

Cov.:

AF XY:

0.0542

AC XY:

2167

AN XY:

39996

show subpopulations

African (AFR)

AF:

0.207

AC:

4520

AN:

21828

American (AMR)

AF:

0.0300

AC:

215

AN:

7156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2530

East Asian (EAS)

AF:

0.000807

AC:

AN:

3716

South Asian (SAS)

AF:

0.00

AC:

AN:

2166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4488

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

248

European-Non Finnish (NFE)

AF:

0.000974

AC:

AN:

46214

Other (OTH)

AF:

0.0638

AC:

AN:

1112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

187

373

560

746

933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0514

Hom.:

ExAC

AF:

0.00375

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary von Willebrand disease

Benign:2

Aug 12, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000552.5(VWF):c.3485C>T is a missense variant that replaces proline with leucine at position 1162. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.2036 (based on 7087/34136 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). Heterologous expression of the variant protein revealed similarities to the wild-type VWF control in secretion, collagen binding, GPIb binding, and multimerization (PMID: 28544236). The computational predictor REVEL gives a score of 0.677, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, PP3. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

von Willebrand disease type 1

Benign:1

Dec 10, 2020

Laboratory of Hematology, Radboud University Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0019

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.5

PhyloP100

6.4

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.22

MPC

0.94

ClinPred

0.028

GERP RS

4.9

Varity_R

0.30

gMVP

0.58

Mutation Taster

=77/23

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