rs7980045

Positions:

• chr12-6095449-T-G

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.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 NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.11

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 12-6095449-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	UniProt
VWF	NM_000552.5	c.657+11A>C		intron_variant		ENST00000261405.10
VWF	XM_047429501.1	c.657+11A>C		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0996 AC: 15135 AN: 151956 Hom.: 1615 Cov.: 31

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

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.: 31 AF XY: 0.0386 AC XY: 28066 AN XY: 727196

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.: 31 AF XY: 0.0962 AC XY: 7151 AN XY: 74342

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2019

- -

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

Other links and lift over

dbSNP: rs7980045; hg19: chr12-6204615; COSMIC: COSV105047018; COSMIC: COSV105047018;