rs216902

Positions:

• chr12-5996221-G-A
• chr12-5996221-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.5844C>T​(p.Cys1948=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,607,762 control chromosomes in the GnomAD database, including 133,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11845 hom., cov: 32)
  • Exomes 𝑓: 0.40 (121815 hom.)
• Consequence: VWF NM_000552.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001009
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-5996221-G-A is Benign according to our data. Variant chr12-5996221-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5996221-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.5844C>T	p.Cys1948=	splice_region_variant, synonymous_variant	35/52	ENST00000261405.10
VWF	XM_047429501.1	c.5844C>T	p.Cys1948=	splice_region_variant, synonymous_variant	35/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.5844C>T	p.Cys1948=	splice_region_variant, synonymous_variant	35/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-2287C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58298 AN: 151844 Hom.: 11821 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.378

GnomAD3 exomes AF: 0.438 AC: 106712 AN: 243910 Hom.: 24803 AF XY: 0.438 AC XY: 57648 AN XY: 131722

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.526

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.401 AC: 583244 AN: 1455798 Hom.: 121815 Cov.: 39 AF XY: 0.404 AC XY: 292222 AN XY: 723872

Gnomad4 AFR exome AF: 0.307

Gnomad4 AMR exome AF: 0.515

Gnomad4 ASJ exome AF: 0.329

Gnomad4 EAS exome AF: 0.783

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.384 AC: 58365 AN: 151964 Hom.: 11845 Cov.: 32 AF XY: 0.392 AC XY: 29118 AN XY: 74290

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.382

Alfa AF: 0.383 Hom.: 24302

Bravo AF: 0.382

Asia WGS AF: 0.577 AC: 2003 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0
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: rs216902; hg19: chr12-6105387; COSMIC: COSV54620567;