rs55687637

Positions:

• chr12-5967474-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000552.5(VWF):​c.7887+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,368 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 32)
  • Exomes 𝑓: 0.010 (90 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.953

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-5967474-A-G is Benign according to our data. Variant chr12-5967474-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256701.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chr12-5967474-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1231 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.7887+12T>C		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.7887+12T>C		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.7887+12T>C		intron_variant		1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000621700.1	n.205+12T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 1232 AN: 152082 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00777 AC: 1951 AN: 251224 Hom.: 13 AF XY: 0.00772 AC XY: 1049 AN XY: 135824

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00517

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.0103 AC: 15017 AN: 1461168 Hom.: 90 Cov.: 32 AF XY: 0.0102 AC XY: 7397 AN XY: 726942

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.00714

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00952

GnomAD4 genome AF: 0.00809 AC: 1231 AN: 152200 Hom.: 7 Cov.: 32 AF XY: 0.00775 AC XY: 577 AN XY: 74416

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00991 Hom.: 2

Bravo AF: 0.00804

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	VWF: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Hereditary von Willebrand disease Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.46

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: rs55687637; hg19: chr12-6076640;