rs216900

Positions:

• chr12-5993736-C-T

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.6598+126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 806,516 control chromosomes in the GnomAD database, including 2,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (453 hom., cov: 30)
  • Exomes 𝑓: 0.081 (2511 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.412

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=-0.88).
• BP6: Variant 12-5993736-C-T is Benign according to our data. Variant chr12-5993736-C-T is described in ClinVar as [Benign]. Clinvar id is 1250723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.6598+126G>A		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6598+126G>A		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6598+126G>A		intron_variant		1	NM_000552.5	ENSP00000261405	P1

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9732 AN: 150858 Hom.: 453 Cov.: 30

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.00234

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0490

GnomAD4 exome AF: 0.0808 AC: 52966 AN: 655542 Hom.: 2511 AF XY: 0.0803 AC XY: 27842 AN XY: 346830

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0833

Gnomad4 ASJ exome AF: 0.0448

Gnomad4 EAS exome AF: 0.000553

Gnomad4 SAS exome AF: 0.0563

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.0921

Gnomad4 OTH exome AF: 0.0681

GnomAD4 genome AF: 0.0645 AC: 9734 AN: 150974 Hom.: 453 Cov.: 30 AF XY: 0.0643 AC XY: 4736 AN XY: 73686

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0652

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.00234

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0917

Gnomad4 OTH AF: 0.0485

Alfa AF: 0.0875 Hom.: 105

Bravo AF: 0.0571

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.68

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: rs216900; hg19: chr12-6102902;