12-6057952-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000552.5(VWF):c.1626G>A(p.Ala542Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,613,666 control chromosomes in the GnomAD database, including 6,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.070 ( 437 hom., cov: 31)

Exomes 𝑓: 0.090 ( 6488 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0730

Publications

9 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 12-6057952-C-T is Benign according to our data. Variant chr12-6057952-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.073 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.1626G>A	p.Ala542Ala	synonymous_variant	Exon 14 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.1626G>A	p.Ala542Ala	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.1626G>A	p.Ala542Ala	synonymous_variant	Exon 14 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.420+52563G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0703

AC:

10696

AN:

152136

Hom.:

440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0422

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.0959

Gnomad FIN

AF:

0.0680

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0882

Gnomad OTH

AF:

0.0642

GnomAD2 exomes

AF:

0.0792

AC:

19825

AN:

250416

AF XY:

0.0816

show subpopulations

Gnomad AFR exome

AF:

0.0422

Gnomad AMR exome

AF:

0.0301

Gnomad ASJ exome

AF:

0.0279

Gnomad EAS exome

AF:

0.146

Gnomad FIN exome

AF:

0.0768

Gnomad NFE exome

AF:

0.0907

Gnomad OTH exome

AF:

0.0738

GnomAD4 exome

AF:

0.0905

AC:

132254

AN:

1461412

Hom.:

6488

Cov.:

AF XY:

0.0904

AC XY:

65708

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.0427

AC:

1428

AN:

33480

American (AMR)

AF:

0.0308

AC:

1378

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0272

AC:

710

AN:

26136

East Asian (EAS)

AF:

0.140

AC:

5559

AN:

39700

South Asian (SAS)

AF:

0.0900

AC:

7760

AN:

86256

European-Finnish (FIN)

AF:

0.0757

AC:

4009

AN:

52962

Middle Eastern (MID)

AF:

0.0383

AC:

221

AN:

5766

European-Non Finnish (NFE)

AF:

0.0952

AC:

105880

AN:

1111998

Other (OTH)

AF:

0.0879

AC:

5309

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

7295

14589

21884

29178

36473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0702

AC:

10693

AN:

152254

Hom.:

437

Cov.:

AF XY:

0.0689

AC XY:

5131

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0436

AC:

1813

AN:

41562

American (AMR)

AF:

0.0421

AC:

644

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.147

AC:

758

AN:

5150

South Asian (SAS)

AF:

0.0959

AC:

463

AN:

4826

European-Finnish (FIN)

AF:

0.0680

AC:

722

AN:

10612

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0882

AC:

5997

AN:

68008

Other (OTH)

AF:

0.0640

AC:

135

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

519

1038

1558

2077

2596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0770

Hom.:

284

Bravo

AF:

0.0676

Asia WGS

AF:

0.118

AC:

411

AN:

3478

EpiCase

AF:

0.0816

EpiControl

AF:

0.0831

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 20, 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

- -

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

- -

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

-0.38

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.073

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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12-6057952-C-T

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