rs35335161

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000552.5(VWF):c.7682T>A(p.Phe2561Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,614,120 control chromosomes in the GnomAD database, including 1,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 143 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1582 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.10

Publications

18 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 -19 ACMG points.

PP2

Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease 1, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease type 2M, von Willebrand disease 3, von Willebrand disease type 2N.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029930472).

BP6

Variant 12-5969258-A-T is Benign according to our data. Variant chr12-5969258-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0388 (5909/152320) while in subpopulation NFE AF = 0.0493 (3356/68016). AF 95% confidence interval is 0.0479. There are 143 homozygotes in GnomAd4. There are 2913 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 143 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.7682T>A	p.Phe2561Tyr	missense_variant	Exon 45 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.7682T>A	p.Phe2561Tyr	missense_variant	Exon 45 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.7682T>A	p.Phe2561Tyr	missense_variant	Exon 45 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5907

AN:

152200

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0226

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0375

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.0382

Gnomad NFE

AF:

0.0494

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0373

AC:

9363

AN:

251044

AF XY:

0.0376

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0768

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0458

GnomAD4 exome

AF:

0.0437

AC:

63841

AN:

1461800

Hom.:

1582

Cov.:

AF XY:

0.0429

AC XY:

31195

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0224

AC:

750

AN:

33480

American (AMR)

AF:

0.0256

AC:

1144

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

728

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00407

AC:

351

AN:

86252

European-Finnish (FIN)

AF:

0.0773

AC:

4127

AN:

53386

Middle Eastern (MID)

AF:

0.0196

AC:

113

AN:

5768

European-Non Finnish (NFE)

AF:

0.0489

AC:

54362

AN:

1111962

Other (OTH)

AF:

0.0375

AC:

2266

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3594

7188

10782

14376

17970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1932

3864

5796

7728

9660

<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:

0.0388

AC:

5909

AN:

152320

Hom.:

143

Cov.:

AF XY:

0.0391

AC XY:

2913

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0226

AC:

938

AN:

41584

American (AMR)

AF:

0.0374

AC:

573

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00352

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0760

AC:

807

AN:

10612

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0493

AC:

3356

AN:

68016

Other (OTH)

AF:

0.0360

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

302

604

907

1209

1511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0447

Hom.:

117

Bravo

AF:

0.0355

TwinsUK

AF:

0.0391

AC:

145

ALSPAC

AF:

0.0501

AC:

193

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.0459

AC:

395

ExAC

AF:

0.0377

AC:

4571

Asia WGS

AF:

0.00664

AC:

AN:

3476

EpiCase

AF:

0.0435

EpiControl

AF:

0.0473

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30366922) -

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

- -

Hereditary von Willebrand disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.29

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.086

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

2.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.26

REVEL

Benign

0.11

Sift

Benign

0.53

Sift4G

Benign

0.86

Polyphen

0.11

Vest4

0.12

MPC

0.60

ClinPred

0.0072

GERP RS

4.9

Varity_R

0.10

gMVP

0.61

Mutation Taster

=92/8

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