chr12-5985679-G-A

Position:

chr12-5985679-G-A

Variant summary

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

The NM_000552.5(VWF):c.6799-14C>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.05

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

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/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.6799-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.6799-14C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.6799-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000552.5	ENSP00000261405	P1	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

GnomAD3 exomes

AF:

0.779

AC:

194353

AN:

249600

Hom.:

76336

AF XY:

0.774

AC XY:

104407

AN XY:

134970

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 SAS exome

AF:

0.681

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

Gnomad4 AFR exome

AF:

0.658

Gnomad4 AMR exome

AF:

0.867

Gnomad4 ASJ exome

AF:

0.822

Gnomad4 EAS exome

AF:

0.729

Gnomad4 SAS exome

AF:

0.682

Gnomad4 FIN exome

AF:

0.800

Gnomad4 NFE exome

AF:

0.800

Gnomad4 OTH exome

AF:

0.771

GnomAD4 genome

AF:

0.758

AC:

115297

AN:

152198

Hom.:

43962

Cov.:

AF XY:

0.756

AC XY:

56263

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.673

Gnomad4 AMR

AF:

0.812

Gnomad4 ASJ

AF:

0.826

Gnomad4 EAS

AF:

0.674

Gnomad4 SAS

AF:

0.671

Gnomad4 FIN

AF:

0.793

Gnomad4 NFE

AF:

0.800

Gnomad4 OTH

AF:

0.772

Alfa

AF:

0.776

Hom.:

9009

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

0.11

DANN

Benign

0.56

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