rs1800380

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000552.5(VWF):c.2880G>A(p.Arg960Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,613,814 control chromosomes in the GnomAD database, including 49,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5042 hom., cov: 31)

Exomes 𝑓: 0.24 ( 44836 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: -0.749

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 12-6029429-C-T is Benign according to our data. Variant chr12-6029429-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.749 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2880G>A	p.Arg960Arg	synonymous_variant	Exon 22 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.2880G>A	p.Arg960Arg	synonymous_variant	Exon 22 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2880G>A	p.Arg960Arg	synonymous_variant	Exon 22 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5 link	n.421-35495G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37864

AN:

151868

Hom.:

5039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.250

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.255

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.204

AC:

51204

AN:

251332

AF XY:

0.201

show subpopulations

Gnomad AFR exome

AF:

0.320

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.240

AC:

350235

AN:

1461828

Hom.:

44836

Cov.:

AF XY:

0.236

AC XY:

171420

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.325

AC:

10865

AN:

33480

American (AMR)

AF:

0.131

AC:

5856

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

6382

AN:

26136

East Asian (EAS)

AF:

0.000428

AC:

AN:

39700

South Asian (SAS)

AF:

0.119

AC:

10267

AN:

86258

European-Finnish (FIN)

AF:

0.251

AC:

13391

AN:

53406

Middle Eastern (MID)

AF:

0.189

AC:

1091

AN:

5768

European-Non Finnish (NFE)

AF:

0.259

AC:

288182

AN:

1111962

Other (OTH)

AF:

0.235

AC:

14184

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

15995

31989

47984

63978

79973

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9532

19064

28596

38128

47660

<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:

0.249

AC:

37900

AN:

151986

Hom.:

5042

Cov.:

AF XY:

0.243

AC XY:

18035

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.311

AC:

12872

AN:

41416

American (AMR)

AF:

0.194

AC:

2964

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

829

AN:

3466

East Asian (EAS)

AF:

0.00155

AC:

AN:

5176

South Asian (SAS)

AF:

0.109

AC:

524

AN:

4798

European-Finnish (FIN)

AF:

0.250

AC:

2641

AN:

10576

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.255

AC:

17312

AN:

67964

Other (OTH)

AF:

0.234

AC:

494

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1394

2788

4183

5577

6971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.250

Hom.:

7975

Bravo

AF:

0.250

Asia WGS

AF:

0.0790

AC:

277

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Allele frequency is common in at least one population database (frequency: 32.021% in gnomAD_Exomes) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -

Aug 29, 2018

GeneDx

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

- -

not specified

Benign:2

Sep 29, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.81

(source)

DANN

Benign

0.60

PhyloP100

-0.75

Mutation Taster

=100/0

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