chr12-6044493-G-T

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.2282-42C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,601,648 control chromosomes in the GnomAD database, including 240,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 20148 hom., cov: 32)

Exomes 𝑓: 0.55 ( 220604 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.420

Publications

22 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=-0.84).

BP6

Variant 12-6044493-G-T is Benign according to our data. Variant chr12-6044493-G-T is described in ClinVar as Benign. ClinVar VariationId is 256658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2282-42C>A		intron_variant	Intron 17 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 link	c.2282-42C>A		intron_variant	Intron 17 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2282-42C>A		intron_variant	Intron 17 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5 link	n.421-50559C>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.493

AC:

74953

AN:

151954

Hom.:

20135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.540

Gnomad AMR

AF:

0.645

Gnomad ASJ

AF:

0.643

Gnomad EAS

AF:

0.703

Gnomad SAS

AF:

0.654

Gnomad FIN

AF:

0.537

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.539

GnomAD2 exomes

AF:

0.585

AC:

135035

AN:

230794

AF XY:

0.586

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.740

Gnomad ASJ exome

AF:

0.648

Gnomad EAS exome

AF:

0.722

Gnomad FIN exome

AF:

0.533

Gnomad NFE exome

AF:

0.545

Gnomad OTH exome

AF:

0.590

GnomAD4 exome

AF:

0.547

AC:

793387

AN:

1449576

Hom.:

220604

Cov.:

AF XY:

0.550

AC XY:

396376

AN XY:

720474

show subpopulations

African (AFR)

AF:

0.276

AC:

9149

AN:

33188

American (AMR)

AF:

0.723

AC:

31229

AN:

43174

Ashkenazi Jewish (ASJ)

AF:

0.649

AC:

16836

AN:

25932

East Asian (EAS)

AF:

0.699

AC:

27398

AN:

39222

South Asian (SAS)

AF:

0.629

AC:

53433

AN:

84950

European-Finnish (FIN)

AF:

0.525

AC:

27306

AN:

51984

Middle Eastern (MID)

AF:

0.649

AC:

3680

AN:

5674

European-Non Finnish (NFE)

AF:

0.535

AC:

591373

AN:

1105520

Other (OTH)

AF:

0.550

AC:

32983

AN:

59932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

19729

39458

59188

78917

98646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16880

33760

50640

67520

84400

<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:

0.493

AC:

74994

AN:

152072

Hom.:

20148

Cov.:

AF XY:

0.501

AC XY:

37251

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.283

AC:

11735

AN:

41496

American (AMR)

AF:

0.646

AC:

9880

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.643

AC:

2230

AN:

3468

East Asian (EAS)

AF:

0.705

AC:

3623

AN:

5142

South Asian (SAS)

AF:

0.654

AC:

3149

AN:

4816

European-Finnish (FIN)

AF:

0.537

AC:

5684

AN:

10584

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36871

AN:

67956

Other (OTH)

AF:

0.538

AC:

1135

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1844

3687

5531

7374

9218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.513

Hom.:

29005

Bravo

AF:

0.491

Asia WGS

AF:

0.640

AC:

2226

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.9

(source)

DANN

Benign

0.59

PhyloP100

-0.42

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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