chr12-6044348-A-G

Variant names:

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.2385T>C(p.Tyr795Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,920 control chromosomes in the GnomAD database, including 108,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13207 hom., cov: 33)

Exomes 𝑓: 0.35 ( 94802 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.14

Publications

54 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=-0.62).

BP6

Variant 12-6044348-A-G is Benign according to our data. Variant chr12-6044348-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.2385T>C	p.Tyr795Tyr	synonymous	Exon 18 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.2385T>C	p.Tyr795Tyr	synonymous	Exon 18 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-50414T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.395

AC:

60027

AN:

151964

Hom.:

13180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.576

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.294

Gnomad EAS

AF:

0.0782

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.372

GnomAD2 exomes

AF:

0.312

AC:

78487

AN:

251290

AF XY:

0.311

show subpopulations

Gnomad AFR exome

AF:

0.582

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.0702

Gnomad FIN exome

AF:

0.361

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.324

GnomAD4 exome

AF:

0.352

AC:

514131

AN:

1461838

Hom.:

94802

Cov.:

AF XY:

0.348

AC XY:

253414

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.583

AC:

19511

AN:

33480

American (AMR)

AF:

0.190

AC:

8476

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

7687

AN:

26136

East Asian (EAS)

AF:

0.0709

AC:

2813

AN:

39700

South Asian (SAS)

AF:

0.249

AC:

21483

AN:

86256

European-Finnish (FIN)

AF:

0.358

AC:

19118

AN:

53408

Middle Eastern (MID)

AF:

0.282

AC:

1628

AN:

5766

European-Non Finnish (NFE)

AF:

0.371

AC:

412233

AN:

1111978

Other (OTH)

AF:

0.351

AC:

21182

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

20254

40508

60762

81016

101270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12930

25860

38790

51720

64650

<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:

0.395

AC:

60093

AN:

152082

Hom.:

13207

Cov.:

AF XY:

0.387

AC XY:

28797

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.576

AC:

23874

AN:

41472

American (AMR)

AF:

0.269

AC:

4116

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

1022

AN:

3472

East Asian (EAS)

AF:

0.0774

AC:

401

AN:

5182

South Asian (SAS)

AF:

0.236

AC:

1139

AN:

4820

European-Finnish (FIN)

AF:

0.354

AC:

3740

AN:

10574

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.362

AC:

24597

AN:

67952

Other (OTH)

AF:

0.368

AC:

778

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1775

3549

5324

7098

8873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.385

Hom.:

17268

Bravo

AF:

0.399

Asia WGS

AF:

0.204

AC:

710

AN:

3478

EpiCase

AF:

0.354

EpiControl

AF:

0.362

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

Mar 02, 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

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: 58.183% 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.

Oct 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.14

(source)

DANN

Benign

0.73

PhyloP100

-1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over