rs1800379

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1548T>C(p.Tyr516Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,612,916 control chromosomes in the GnomAD database, including 111,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 14101 hom., cov: 32)

Exomes 𝑓: 0.36 ( 97445 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 0.193

Publications

13 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=-0.88).

BP6

Variant 12-6058030-A-G is Benign according to our data. Variant chr12-6058030-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.193 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.1548T>C	p.Tyr516Tyr	synonymous_variant	Exon 14 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.1548T>C	p.Tyr516Tyr	synonymous_variant	Exon 14 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.1548T>C	p.Tyr516Tyr	synonymous_variant	Exon 14 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.420+52485T>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.410

AC:

62259

AN:

152026

Hom.:

14071

Cov.:

show subpopulations

Gnomad AFR

AF:

0.597

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.275

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.396

GnomAD2 exomes

AF:

0.334

AC:

82849

AN:

248268

AF XY:

0.335

show subpopulations

Gnomad AFR exome

AF:

0.608

Gnomad AMR exome

AF:

0.173

Gnomad ASJ exome

AF:

0.341

Gnomad EAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.366

Gnomad NFE exome

AF:

0.368

Gnomad OTH exome

AF:

0.343

GnomAD4 exome

AF:

0.359

AC:

524289

AN:

1460772

Hom.:

97445

Cov.:

AF XY:

0.357

AC XY:

259598

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.613

AC:

20522

AN:

33480

American (AMR)

AF:

0.185

AC:

8277

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

8802

AN:

26136

East Asian (EAS)

AF:

0.176

AC:

6977

AN:

39700

South Asian (SAS)

AF:

0.310

AC:

26723

AN:

86256

European-Finnish (FIN)

AF:

0.368

AC:

19258

AN:

52358

Middle Eastern (MID)

AF:

0.321

AC:

1853

AN:

5768

European-Non Finnish (NFE)

AF:

0.369

AC:

409822

AN:

1111972

Other (OTH)

AF:

0.365

AC:

22055

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

19935

39869

59804

79738

99673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12956

25912

38868

51824

64780

<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:

0.410

AC:

62330

AN:

152144

Hom.:

14101

Cov.:

AF XY:

0.402

AC XY:

29918

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.598

AC:

24799

AN:

41482

American (AMR)

AF:

0.274

AC:

4197

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1147

AN:

3468

East Asian (EAS)

AF:

0.185

AC:

959

AN:

5174

South Asian (SAS)

AF:

0.300

AC:

1448

AN:

4828

European-Finnish (FIN)

AF:

0.356

AC:

3774

AN:

10596

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.363

AC:

24711

AN:

67986

Other (OTH)

AF:

0.392

AC:

828

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1819

3638

5458

7277

9096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.372

Hom.:

39221

Bravo

AF:

0.410

Asia WGS

AF:

0.293

AC:

1023

AN:

3478

EpiCase

AF:

0.355

EpiControl

AF:

0.363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 25, 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

- -

Oct 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 60.792% 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. -

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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

-0.88

CADD

Benign

0.74

(source)

DANN

Benign

0.48

PhyloP100

0.19

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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