rs216325

chr12-6036363-G-Achr12-6036363-G-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.2546+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,609,928 control chromosomes in the GnomAD database, including 365,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38221 hom., cov: 33)
  • Exomes 𝑓: 0.67 (327528 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.15

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=-0.92).
• BP6: Variant 12-6036363-G-A is Benign according to our data. Variant chr12-6036363-G-A is described in ClinVar as [Benign]. Clinvar id is 256661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2546+25C>T		intron_variant		ENST00000261405.10
VWF	XM_047429501.1	c.2546+25C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2546+25C>T		intron_variant		1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-42429C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107340 AN: 152014 Hom.: 38193 Cov.: 33

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.719

GnomAD3 exomes AF: 0.706 AC: 176978 AN: 250800 Hom.: 63065 AF XY: 0.703 AC XY: 95279 AN XY: 135572

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.747

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.696

GnomAD4 exome AF: 0.668 AC: 974067 AN: 1457796 Hom.: 327528 Cov.: 32 AF XY: 0.670 AC XY: 485977 AN XY: 725516

Gnomad4 AFR exome AF: 0.768

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.707

Gnomad4 EAS exome AF: 0.794

Gnomad4 SAS exome AF: 0.740

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.706 AC: 107417 AN: 152132 Hom.: 38221 Cov.: 33 AF XY: 0.711 AC XY: 52860 AN XY: 74386

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.745

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.790

Gnomad4 SAS AF: 0.762

Gnomad4 FIN AF: 0.648

Gnomad4 NFE AF: 0.654

Gnomad4 OTH AF: 0.716

Alfa AF: 0.671 Hom.: 34343

Bravo AF: 0.716

Asia WGS AF: 0.770 AC: 2676 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.012
Dann	Benign	0.75

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: rs216325; hg19: chr12-6145529;