12-5952393-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg) variant in VWF is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 2705. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1227 (based on 11352/91062 alleles in the South Asian population, including 829 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. As reported in PMID:26105150 the variant is significantly associated with lower plasma levels of FVIII but not vWF. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6401404/MONDO:0019565/090

Frequency

Genomes: 𝑓 0.045 ( 204 hom., cov: 32)

Exomes 𝑓: 0.059 ( 3022 hom. )

Consequence

VWF
NM_000552.5 missense, splice_region

Scores

Splicing: ADA: 0.9526

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 5.94

Publications

27 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 -8 ACMG points.

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.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	Exon 49 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	Exon 49 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 link	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	Exon 49 of 52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000612016.1 link	n.522G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5
VWF	ENST00000621700.1 link	n.431G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0448

AC:

6807

AN:

152098

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0177

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.0433

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.0612

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0449

GnomAD2 exomes

AF:

0.0593

AC:

14897

AN:

251422

AF XY:

0.0641

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.0702

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.00321

Gnomad FIN exome

AF:

0.0595

Gnomad NFE exome

AF:

0.0558

Gnomad OTH exome

AF:

0.0518

GnomAD4 exome

AF:

0.0591

AC:

86371

AN:

1461538

Hom.:

3022

Cov.:

AF XY:

0.0611

AC XY:

44423

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.0162

AC:

543

AN:

33472

American (AMR)

AF:

0.0654

AC:

2923

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0333

AC:

869

AN:

26132

East Asian (EAS)

AF:

0.00202

AC:

AN:

39688

South Asian (SAS)

AF:

0.125

AC:

10779

AN:

86244

European-Finnish (FIN)

AF:

0.0591

AC:

3156

AN:

53382

Middle Eastern (MID)

AF:

0.0584

AC:

337

AN:

5768

European-Non Finnish (NFE)

AF:

0.0577

AC:

64182

AN:

1111760

Other (OTH)

AF:

0.0580

AC:

3502

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4731

9462

14194

18925

23656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2434

4868

7302

9736

12170

<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:

0.0447

AC:

6798

AN:

152216

Hom.:

204

Cov.:

AF XY:

0.0448

AC XY:

3332

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0176

AC:

730

AN:

41532

American (AMR)

AF:

0.0432

AC:

661

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3470

East Asian (EAS)

AF:

0.00289

AC:

AN:

5184

South Asian (SAS)

AF:

0.119

AC:

573

AN:

4818

European-Finnish (FIN)

AF:

0.0612

AC:

649

AN:

10608

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0568

AC:

3860

AN:

67990

Other (OTH)

AF:

0.0445

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

336

672

1008

1344

1680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0517

Hom.:

968

Bravo

AF:

0.0414

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0602

AC:

232

ESP6500AA

AF:

0.0197

AC:

ESP6500EA

AF:

0.0578

AC:

497

ExAC

AF:

0.0593

AC:

7197

Asia WGS

AF:

0.0530

AC:

186

AN:

3478

EpiCase

AF:

0.0601

EpiControl

AF:

0.0566

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.8113G>A (p.Gly2705Arg) variant in VWF is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 2705. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1227 (based on 11352/91062 alleles in the South Asian population, including 829 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. As reported in PMID: 26105150 the variant is significantly associated with lower plasma levels of FVIII but not vWF. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1 -

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

- -

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 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.1

PhyloP100

5.9

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.30

MutPred

0.39

Gain of catalytic residue at L2702 (P = 0.0017);

MPC

1.0

ClinPred

0.024

GERP RS

5.5

Varity_R

0.53

gMVP

0.93

Mutation Taster

=29/71

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.79

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