chr12-6036363-G-A

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.2546+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,609,928 control chromosomes in the GnomAD database, including 365,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38221 hom., cov: 33)

Exomes 𝑓: 0.67 ( 327528 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -4.15

Publications

11 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=-0.92).

BP6

Variant 12-6036363-G-A is Benign according to our data. Variant chr12-6036363-G-A is described in ClinVar as Benign. ClinVar VariationId is 256661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2546+25C>T		intron_variant	Intron 19 of 51	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2546+25C>T		intron_variant	Intron 19 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2546+25C>T		intron_variant	Intron 19 of 51	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-42429C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.706

AC:

107340

AN:

152014

Hom.:

38193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.774

Gnomad AMI

AF:

0.703

Gnomad AMR

AF:

0.744

Gnomad ASJ

AF:

0.706

Gnomad EAS

AF:

0.789

Gnomad SAS

AF:

0.762

Gnomad FIN

AF:

0.648

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.654

Gnomad OTH

AF:

0.719

GnomAD2 exomes

AF:

0.706

AC:

176978

AN:

250800

AF XY:

0.703

show subpopulations

Gnomad AFR exome

AF:

0.771

Gnomad AMR exome

AF:

0.803

Gnomad ASJ exome

AF:

0.704

Gnomad EAS exome

AF:

0.792

Gnomad FIN exome

AF:

0.645

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.696

GnomAD4 exome

AF:

0.668

AC:

974067

AN:

1457796

Hom.:

327528

Cov.:

AF XY:

0.670

AC XY:

485977

AN XY:

725516

show subpopulations

African (AFR)

AF:

0.768

AC:

25673

AN:

33408

American (AMR)

AF:

0.795

AC:

35523

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.707

AC:

18451

AN:

26110

East Asian (EAS)

AF:

0.794

AC:

31490

AN:

39674

South Asian (SAS)

AF:

0.740

AC:

63753

AN:

86164

European-Finnish (FIN)

AF:

0.638

AC:

34011

AN:

53296

Middle Eastern (MID)

AF:

0.737

AC:

4165

AN:

5648

European-Non Finnish (NFE)

AF:

0.650

AC:

719995

AN:

1108536

Other (OTH)

AF:

0.681

AC:

41006

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

16501

33002

49502

66003

82504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18996

37992

56988

75984

94980

<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:

0.706

AC:

107417

AN:

152132

Hom.:

38221

Cov.:

AF XY:

0.711

AC XY:

52860

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.774

AC:

32120

AN:

41512

American (AMR)

AF:

0.745

AC:

11384

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

2450

AN:

3472

East Asian (EAS)

AF:

0.790

AC:

4085

AN:

5174

South Asian (SAS)

AF:

0.762

AC:

3672

AN:

4820

European-Finnish (FIN)

AF:

0.648

AC:

6851

AN:

10578

Middle Eastern (MID)

AF:

0.741

AC:

218

AN:

294

European-Non Finnish (NFE)

AF:

0.654

AC:

44483

AN:

67966

Other (OTH)

AF:

0.716

AC:

1513

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1597

3194

4790

6387

7984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.677

Hom.:

45512

Bravo

AF:

0.716

Asia WGS

AF:

0.770

AC:

2676

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 06, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.92

CADD

Benign

0.012

(source)

DANN

Benign

0.75

PhyloP100

-4.2

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