NM_000552.5:c.6799-14C>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.6799-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 1,612,346 control chromosomes in the GnomAD database, including 500,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 43962 hom., cov: 33)

Exomes 𝑓: 0.79 ( 456519 hom. )

Consequence

VWF
NM_000552.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.05

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 12-5985679-G-A is Benign according to our data. Variant chr12-5985679-G-A is described in ClinVar as Benign. ClinVar VariationId is 256693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.6799-14C>T		intron_variant	Intron 38 of 51	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.6799-14C>T		intron_variant	Intron 38 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.6799-14C>T		intron_variant	Intron 38 of 51	1	NM_000552.5	ENSP00000261405.5		P04275-1

Frequencies

GnomAD3 genomes

AF:

0.758

AC:

115204

AN:

152080

Hom.:

43924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.673

Gnomad AMI

AF:

0.783

Gnomad AMR

AF:

0.811

Gnomad ASJ

AF:

0.826

Gnomad EAS

AF:

0.673

Gnomad SAS

AF:

0.671

Gnomad FIN

AF:

0.793

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.800

Gnomad OTH

AF:

0.771

GnomAD2 exomes

AF:

0.779

AC:

194353

AN:

249600

AF XY:

0.774

show subpopulations

Gnomad AFR exome

AF:

0.671

Gnomad AMR exome

AF:

0.873

Gnomad ASJ exome

AF:

0.821

Gnomad EAS exome

AF:

0.674

Gnomad FIN exome

AF:

0.798

Gnomad NFE exome

AF:

0.801

Gnomad OTH exome

AF:

0.785

GnomAD4 exome

AF:

0.789

AC:

1152384

AN:

1460148

Hom.:

456519

Cov.:

AF XY:

0.786

AC XY:

570996

AN XY:

726442

show subpopulations

African (AFR)

AF:

0.658

AC:

22015

AN:

33444

American (AMR)

AF:

0.867

AC:

38758

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.822

AC:

21475

AN:

26126

East Asian (EAS)

AF:

0.729

AC:

28915

AN:

39676

South Asian (SAS)

AF:

0.682

AC:

58802

AN:

86184

European-Finnish (FIN)

AF:

0.800

AC:

42531

AN:

53174

Middle Eastern (MID)

AF:

0.731

AC:

4210

AN:

5762

European-Non Finnish (NFE)

AF:

0.800

AC:

889133

AN:

1110754

Other (OTH)

AF:

0.771

AC:

46545

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

12139

24279

36418

48558

60697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20708

41416

62124

82832

103540

<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:

0.758

AC:

115297

AN:

152198

Hom.:

43962

Cov.:

AF XY:

0.756

AC XY:

56263

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.673

AC:

27937

AN:

41524

American (AMR)

AF:

0.812

AC:

12418

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.826

AC:

2865

AN:

3468

East Asian (EAS)

AF:

0.674

AC:

3476

AN:

5160

South Asian (SAS)

AF:

0.671

AC:

3241

AN:

4830

European-Finnish (FIN)

AF:

0.793

AC:

8401

AN:

10588

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.800

AC:

54427

AN:

68010

Other (OTH)

AF:

0.772

AC:

1630

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1424

2847

4271

5694

7118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.774

Hom.:

9182

Bravo

AF:

0.759

Asia WGS

AF:

0.696

AC:

2422

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.11

(source)

DANN

Benign

0.56

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

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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