rs11063962

chr12-5967615-G-A

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.7771-13C>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 0.0787 in 1,611,768 control chromosomes in the GnomAD database, including 5,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (298 hom., cov: 32)
  • Exomes 𝑓: 0.081 (5121 hom.)
• Consequence: VWF NM_000552.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.704

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=-0.86).
• BP6: Variant 12-5967615-G-A is Benign according to our data. Variant chr12-5967615-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5967615-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.7771-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261405.10
VWF	XM_047429501.1	c.7771-13C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.7771-13C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000552.5	P1
VWF	ENST00000621700.1	n.89-13C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0567 AC: 8622 AN: 152046 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0489

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0540

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.0643

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0561

GnomAD3 exomes AF: 0.0642 AC: 16039 AN: 249854 Hom.: 617 AF XY: 0.0681 AC XY: 9208 AN XY: 135246

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.0496

Gnomad SAS exome AF: 0.0915

Gnomad FIN exome AF: 0.0713

Gnomad NFE exome AF: 0.0778

Gnomad OTH exome AF: 0.0664

GnomAD4 exome AF: 0.0810 AC: 118185 AN: 1459604 Hom.: 5121 Cov.: 32 AF XY: 0.0815 AC XY: 59155 AN XY: 726236

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.0324

Gnomad4 ASJ exome AF: 0.0368

Gnomad4 EAS exome AF: 0.0514

Gnomad4 SAS exome AF: 0.0902

Gnomad4 FIN exome AF: 0.0692

Gnomad4 NFE exome AF: 0.0874

Gnomad4 OTH exome AF: 0.0739

GnomAD4 genome AF: 0.0566 AC: 8618 AN: 152164 Hom.: 298 Cov.: 32 AF XY: 0.0555 AC XY: 4124 AN XY: 74372

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.0488

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.0544

Gnomad4 SAS AF: 0.0929

Gnomad4 FIN AF: 0.0643

Gnomad4 NFE AF: 0.0803

Gnomad4 OTH AF: 0.0550

Alfa AF: 0.0618 Hom.: 53

Bravo AF: 0.0531

Asia WGS AF: 0.0700 AC: 250 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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

- -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.54
Dann	Benign	0.70

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: rs11063962; hg19: chr12-6076781;