rs11063962

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000552.5(VWF):c.7771-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0787 in 1,611,768 control chromosomes in the GnomAD database, including 5,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 298 hom., cov: 32)

Exomes 𝑓: 0.081 ( 5121 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.704

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-5967615-G-A is Benign according to our data. Variant chr12-5967615-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.7771-13C>T		intron_variant	Intron 46 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.7771-13C>T		intron_variant	Intron 46 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.7771-13C>T		intron_variant	Intron 46 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000621700.1 link	n.89-13C>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0567

AC:

8622

AN:

152046

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.0340

Gnomad EAS

AF:

0.0540

Gnomad SAS

AF:

0.0934

Gnomad FIN

AF:

0.0643

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0803

Gnomad OTH

AF:

0.0561

GnomAD2 exomes

AF:

0.0642

AC:

16039

AN:

249854

AF XY:

0.0681

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0311

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.0496

Gnomad FIN exome

AF:

0.0713

Gnomad NFE exome

AF:

0.0778

Gnomad OTH exome

AF:

0.0664

GnomAD4 exome

AF:

0.0810

AC:

118185

AN:

1459604

Hom.:

5121

Cov.:

AF XY:

0.0815

AC XY:

59155

AN XY:

726236

show subpopulations

African (AFR)

AF:

0.0128

AC:

427

AN:

33464

American (AMR)

AF:

0.0324

AC:

1449

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0368

AC:

962

AN:

26134

East Asian (EAS)

AF:

0.0514

AC:

2040

AN:

39696

South Asian (SAS)

AF:

0.0902

AC:

7783

AN:

86242

European-Finnish (FIN)

AF:

0.0692

AC:

3602

AN:

52076

Middle Eastern (MID)

AF:

0.0597

AC:

342

AN:

5732

European-Non Finnish (NFE)

AF:

0.0874

AC:

97119

AN:

1111194

Other (OTH)

AF:

0.0739

AC:

4461

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

5399

10798

16198

21597

26996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3676

7352

11028

14704

18380

<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:

0.0566

AC:

8618

AN:

152164

Hom.:

298

Cov.:

AF XY:

0.0555

AC XY:

4124

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0159

AC:

662

AN:

41528

American (AMR)

AF:

0.0488

AC:

746

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

118

AN:

3472

East Asian (EAS)

AF:

0.0544

AC:

281

AN:

5170

South Asian (SAS)

AF:

0.0929

AC:

447

AN:

4814

European-Finnish (FIN)

AF:

0.0643

AC:

682

AN:

10600

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0803

AC:

5458

AN:

67980

Other (OTH)

AF:

0.0550

AC:

116

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

404

808

1211

1615

2019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0725

Hom.:

623

Bravo

AF:

0.0531

Asia WGS

AF:

0.0700

AC:

250

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

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

- -

Hereditary von Willebrand disease

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.54

(source)

DANN

Benign

0.70

PhyloP100

-0.70

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