rs55687637

Variant names:

• chr12-5967474-A-G
• rs55687637
• NM_000552.5:c.7887+12T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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

Our verdict: Benign. The variant received -13 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: {Uncertain_significance=1, Benign=3}. Variant chr12-5967474-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00809 (1231/152200) while in subpopulation NFE AF = 0.0124 (844/67984). AF 95% confidence interval is 0.0117. There are 7 homozygotes in GnomAd4. There are 577 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1231 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.7887+12T>C		intron_variant	Intron 47 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.7887+12T>C		intron_variant	Intron 47 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.7887+12T>C		intron_variant	Intron 47 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000621700.1	n.205+12T>C		intron_variant	Intron 2 of 3	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

GnomAD2 exomes AF: 0.00777 AC: 1951 AN: 251224 AF XY: 0.00772

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 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 AC: 53 AN: 33470

Gnomad4 AMR exome AF: 0.00566 AC: 253 AN: 44722

Gnomad4 ASJ exome AF: 0.0107 AC: 279 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.00239 AC: 206 AN: 86248

Gnomad4 FIN exome AF: 0.00714 AC: 381 AN: 53396

Gnomad4 NFE exome AF: 0.0119 AC: 13197 AN: 1111366

Gnomad4 Remaining exome AF: 0.00952 AC: 575 AN: 60378

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 AC: 0.00192558 AN: 0.00192558

Gnomad4 AMR AF: 0.00759 AC: 0.00758666 AN: 0.00758666

Gnomad4 ASJ AF: 0.0112 AC: 0.0112457 AN: 0.0112457

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00166 AC: 0.00166044 AN: 0.00166044

Gnomad4 FIN AF: 0.00764 AC: 0.00763575 AN: 0.00763575

Gnomad4 NFE AF: 0.0124 AC: 0.0124147 AN: 0.0124147

Gnomad4 OTH AF: 0.0109 AC: 0.0108696 AN: 0.0108696

Alfa AF: 0.00923 Hom.: 6

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

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VWF: BS1, BS2 -

Sep 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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
Mutation Taster		=100/0	polymorphism

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;