chr12-6095449-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000321023.5(VWF):n.*727A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,613,852 control chromosomes in the GnomAD database, including 3,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1623 hom., cov: 31)

Exomes 𝑓: 0.039 ( 2280 hom. )

Consequence

VWF
ENST00000321023.5 non_coding_transcript_exon

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.11

Publications

4 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 links:

RN7SL69P (HGNC:46085): (RNA, 7SL, cytoplasmic 69, pseudogene)

RN7SL69P 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 12-6095449-T-G is Benign according to our data. Variant chr12-6095449-T-G is described in ClinVar as Benign. ClinVar VariationId is 256691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.657+11A>C		intron_variant	Intron 6 of 51	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.657+11A>C		intron_variant	Intron 6 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.657+11A>C		intron_variant	Intron 6 of 51	1	NM_000552.5	ENSP00000261405.5		P04275-1

Frequencies

GnomAD3 genomes

AF:

0.0996

AC:

15135

AN:

151956

Hom.:

1615

Cov.:

show subpopulations

Gnomad AFR

AF:

0.269

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0567

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.00194

Gnomad SAS

AF:

0.0338

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0887

GnomAD2 exomes

AF:

0.0459

AC:

11540

AN:

251480

AF XY:

0.0411

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.0343

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.0206

Gnomad NFE exome

AF:

0.0346

Gnomad OTH exome

AF:

0.0407

GnomAD4 exome

AF:

0.0392

AC:

57340

AN:

1461778

Hom.:

2280

Cov.:

AF XY:

0.0386

AC XY:

28066

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.277

AC:

9274

AN:

33478

American (AMR)

AF:

0.0370

AC:

1655

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

556

AN:

26132

East Asian (EAS)

AF:

0.000328

AC:

AN:

39692

South Asian (SAS)

AF:

0.0392

AC:

3377

AN:

86254

European-Finnish (FIN)

AF:

0.0201

AC:

1074

AN:

53412

Middle Eastern (MID)

AF:

0.0716

AC:

413

AN:

5768

European-Non Finnish (NFE)

AF:

0.0341

AC:

37900

AN:

1111932

Other (OTH)

AF:

0.0510

AC:

3078

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3136

6272

9409

12545

15681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1516

3032

4548

6064

7580

<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:

0.0998

AC:

15180

AN:

152074

Hom.:

1623

Cov.:

AF XY:

0.0962

AC XY:

7151

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.269

AC:

11158

AN:

41440

American (AMR)

AF:

0.0565

AC:

864

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3468

East Asian (EAS)

AF:

0.00194

AC:

AN:

5148

South Asian (SAS)

AF:

0.0342

AC:

165

AN:

4818

European-Finnish (FIN)

AF:

0.0186

AC:

197

AN:

10614

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0364

AC:

2472

AN:

67990

Other (OTH)

AF:

0.0878

AC:

185

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

601

1202

1802

2403

3004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0609

Hom.:

1052

Bravo

AF:

0.110

Asia WGS

AF:

0.0400

AC:

139

AN:

3478

EpiCase

AF:

0.0366

EpiControl

AF:

0.0362

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 18, 2019

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

- -

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

0.79

(source)

DANN

Benign

0.86

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