rs1800385

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.4693G>T (p.Val1565Leu) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 is 0.3882 (based on 17604/44790 alleles in the east Asian population, including 3463 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor REVEL gives a score of 0.183, 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 benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402474/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.094 ( 1304 hom., cov: 31)

Exomes 𝑓: 0.11 ( 12925 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 0.997

Publications

32 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.4693G>T	p.Val1565Leu	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.4693G>T	p.Val1565Leu	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.4693G>T	p.Val1565Leu	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-24791G>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0943

AC:

14342

AN:

152016

Hom.:

1294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0231

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.371

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.0374

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0849

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.154

AC:

38488

AN:

250486

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.371

Gnomad ASJ exome

AF:

0.0788

Gnomad EAS exome

AF:

0.385

Gnomad FIN exome

AF:

0.0427

Gnomad NFE exome

AF:

0.0846

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.107

AC:

156186

AN:

1460910

Hom.:

12925

Cov.:

AF XY:

0.109

AC XY:

79001

AN XY:

726682

show subpopulations

African (AFR)

AF:

0.0177

AC:

594

AN:

33468

American (AMR)

AF:

0.354

AC:

15818

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.0769

AC:

2008

AN:

26126

East Asian (EAS)

AF:

0.396

AC:

15700

AN:

39676

South Asian (SAS)

AF:

0.200

AC:

17284

AN:

86224

European-Finnish (FIN)

AF:

0.0450

AC:

2386

AN:

53044

Middle Eastern (MID)

AF:

0.0984

AC:

559

AN:

5680

European-Non Finnish (NFE)

AF:

0.0855

AC:

95052

AN:

1111690

Other (OTH)

AF:

0.112

AC:

6785

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

7992

15984

23975

31967

39959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3884

7768

11652

15536

19420

<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:

0.0944

AC:

14368

AN:

152134

Hom.:

1304

Cov.:

AF XY:

0.100

AC XY:

7464

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0232

AC:

962

AN:

41530

American (AMR)

AF:

0.246

AC:

3757

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

259

AN:

3472

East Asian (EAS)

AF:

0.372

AC:

1904

AN:

5114

South Asian (SAS)

AF:

0.218

AC:

1054

AN:

4824

European-Finnish (FIN)

AF:

0.0374

AC:

397

AN:

10616

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0849

AC:

5769

AN:

67974

Other (OTH)

AF:

0.105

AC:

222

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

611

1221

1832

2442

3053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.0915

Hom.:

801

Bravo

AF:

0.108

TwinsUK

AF:

0.0787

AC:

292

ALSPAC

AF:

0.0843

AC:

325

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.0803

AC:

691

ExAC

AF:

0.144

AC:

17431

Asia WGS

AF:

0.287

AC:

995

AN:

3478

EpiCase

AF:

0.0791

EpiControl

AF:

0.0836

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 17, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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 NM_000552.4(VWF):c.4693G>T (p.Val1565Leu) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 is 0.3882 (based on 17604/44790 alleles in the east Asian population, including 3463 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor REVEL gives a score of 0.183, 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 benign for von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP4. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

- -

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

0.18

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.34

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.22

REVEL

Benign

0.18

Sift

Benign

0.38

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.088

MutPred

0.74

Gain of catalytic residue at V1565 (P = 0.0014);

MPC

0.27

ClinPred

0.0010

GERP RS

1.9

Varity_R

0.22

gMVP

0.76

Mutation Taster

=70/30

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