rs201000688

Positions:

• chr12-6013431-A-G
• chr12-6013431-A-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.5620+50T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,607,146 control chromosomes in the GnomAD database, including 1,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (729 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (579 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.220

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 12-6013431-A-G is Benign according to our data. Variant chr12-6013431-A-G is described in ClinVar as [Benign]. Clinvar id is 256685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.5620+50T>C		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5620+50T>C		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5620+50T>C		intron_variant		1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-19497T>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8501 AN: 151994 Hom.: 731 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.0527

GnomAD3 exomes AF: 0.0144 AC: 3505 AN: 243116 Hom.: 268 AF XY: 0.0110 AC XY: 1451 AN XY: 132480

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00680

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.000558

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00548 AC: 7979 AN: 1455034 Hom.: 579 Cov.: 31 AF XY: 0.00475 AC XY: 3437 AN XY: 723956

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00624

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000663

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000723

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0560 AC: 8520 AN: 152112 Hom.: 729 Cov.: 32 AF XY: 0.0536 AC XY: 3988 AN XY: 74358

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0318 Hom.: 72

Bravo AF: 0.0643

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.45

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: rs201000688; hg19: chr12-6122597;