rs177702

Positions:

• chr12-5985679-G-A
• chr12-5985679-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.05

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]

ACMG classification

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	c.6799-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	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	c.6799-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000552.5	ENSP00000261405	P1

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115204 AN: 152080 Hom.: 43924 Cov.: 33

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

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.: 39 AF XY: 0.786 AC XY: 570996 AN XY: 726442

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.: 33 AF XY: 0.756 AC XY: 56263 AN XY: 74392

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

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

Other links and lift over

dbSNP: rs177702; hg19: chr12-6094845;