chr12-5994115-A-T

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.6345T>A(p.Thr2115Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00783 in 1,614,176 control chromosomes in the GnomAD database, including 850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.043 ( 471 hom., cov: 31)

Exomes 𝑓: 0.0042 ( 379 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: -5.34

Publications

1 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=-0.95).

BP6

Variant 12-5994115-A-T is Benign according to our data. Variant chr12-5994115-A-T is described in ClinVar as Benign. ClinVar VariationId is 256690.Status of the report is reviewed_by_expert_panel, 3 stars.

BP7

Synonymous conserved (PhyloP=-5.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 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.6345T>A	p.Thr2115Thr	synonymous	Exon 37 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.6345T>A	p.Thr2115Thr	synonymous	Exon 37 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.421-181T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0425

AC:

6461

AN:

152174

Hom.:

472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0377

GnomAD2 exomes

AF:

0.0112

AC:

2807

AN:

251256

AF XY:

0.00827

show subpopulations

Gnomad AFR exome

AF:

0.151

Gnomad AMR exome

AF:

0.00781

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00421

AC:

6156

AN:

1461884

Hom.:

379

Cov.:

AF XY:

0.00362

AC XY:

2632

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.145

AC:

4845

AN:

33480

American (AMR)

AF:

0.00892

AC:

399

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000278

AC:

309

AN:

1112010

Other (OTH)

AF:

0.00871

AC:

526

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

358

716

1075

1433

1791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<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:

0.0425

AC:

6475

AN:

152292

Hom.:

471

Cov.:

AF XY:

0.0402

AC XY:

2991

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.147

AC:

6093

AN:

41540

American (AMR)

AF:

0.0176

AC:

270

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68026

Other (OTH)

AF:

0.0373

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

289

578

868

1157

1446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0135

Hom.:

Bravo

AF:

0.0483

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

May 11, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

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

Hereditary von Willebrand disease

Benign:2

Nov 05, 2024

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000552.5(VWF):c.6345T>A, p.Thr2115= variant in VWF is a synonymous variant. TheGrpmax filtering allele frequency in gnomAD v4.1 is 0.1435 (based on 10938/75020 alleles, with 830 homozygotes in the African/African-American population), which is above the ClinGen VWD VCEP threshold of >0.1 for BA1. The computational predictor SpliceAI gives a score of 0.0, which meets criteria for BP7. This variant is classified as benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, BP7

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.013

(source)

DANN

Benign

0.46

PhyloP100

-5.3

Mutation Taster

=85/15

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

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