chr12-6095449-T-G

Position:

chr12-6095449-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000261405.10(VWF):c.657+11A>C variant causes a intron 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
ENST00000261405.10 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 256691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6095449-T-G is described in Lovd as [Benign]. Variant chr12-6095449-T-G is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.657+11A>C		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.657+11A>C		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.657+11A>C	intron_variant		1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000321023.5 linkuse as main transcript	c.*727A>C	3_prime_UTR_variant, NMD_transcript_variant	7/7	1		ENSP00000461331
VWF	ENST00000538635.5 linkuse as main transcript	n.420+15066A>C	intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes

AF:

0.0459

AC:

11540

AN:

251480

Hom.:

763

AF XY:

0.0411

AC XY:

5580

AN XY:

135918

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 SAS exome

AF:

0.0375

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

Gnomad4 AFR exome

AF:

0.277

Gnomad4 AMR exome

AF:

0.0370

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0392

Gnomad4 FIN exome

AF:

0.0201

Gnomad4 NFE exome

AF:

0.0341

Gnomad4 OTH exome

AF:

0.0510

GnomAD4 genome

AF:

0.0998

AC:

15180

AN:

152074

Hom.:

1623

Cov.:

AF XY:

0.0962

AC XY:

7151

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.269

Gnomad4 AMR

AF:

0.0565

Gnomad4 ASJ

AF:

0.0228

Gnomad4 EAS

AF:

0.00194

Gnomad4 SAS

AF:

0.0342

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.0364

Gnomad4 OTH

AF:

0.0878

Alfa

AF:

0.0618

Hom.:

161

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

von Willebrand disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

DANN

Benign

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over