12-5996333-T-C

Position:

• chr12-5996333-T-C

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.5843-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 984,014 control chromosomes in the GnomAD database, including 148,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24257 hom., cov: 31)
  • Exomes 𝑓: 0.54 (124079 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.84

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]

VWF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-5996333-T-C is Benign according to our data. Variant chr12-5996333-T-C is described in ClinVar as [Benign]. Clinvar id is 1225172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.5843-111A>G		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5843-111A>G		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5843-111A>G		intron_variant		1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-2399A>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85352 AN: 151846 Hom.: 24228 Cov.: 31

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.542 AC: 450986 AN: 832050 Hom.: 124079 AF XY: 0.545 AC XY: 234992 AN XY: 431516

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.602

Gnomad4 ASJ exome AF: 0.469

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.593

Gnomad4 FIN exome AF: 0.508

Gnomad4 NFE exome AF: 0.523

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome AF: 0.562 AC: 85425 AN: 151964 Hom.: 24257 Cov.: 31 AF XY: 0.563 AC XY: 41798 AN XY: 74268

Gnomad4 AFR AF: 0.595

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.560

Alfa AF: 0.551 Hom.: 3818

Bravo AF: 0.567

Asia WGS AF: 0.630 AC: 2194 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	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.75
DANN	Benign	0.48

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: rs216903; hg19: chr12-6105499;