12-6047311-C-T

Variant names:

• chr12-6047311-C-T
• rs216298
• NM_000552.5:c.2187-494G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000552.5(VWF):​c.2187-494G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.883 in 152,190 control chromosomes in the GnomAD database, including 59,446 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (59446 hom., cov: 31)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.2187-494G>A		intron_variant	Intron 16 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.2187-494G>A		intron_variant	Intron 16 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.2187-494G>A		intron_variant	Intron 16 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-53377G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.883 AC: 134282 AN: 152072 Hom.: 59408 Cov.: 31

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.909

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.904

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.883 AC: 134377 AN: 152190 Hom.: 59446 Cov.: 31 AF XY: 0.883 AC XY: 65709 AN XY: 74388

African (AFR) AF: 0.841 AC: 34913 AN: 41522

American (AMR) AF: 0.909 AC: 13893 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3255 AN: 3470

East Asian (EAS) AF: 0.782 AC: 4041 AN: 5168

South Asian (SAS) AF: 0.890 AC: 4289 AN: 4820

European-Finnish (FIN) AF: 0.891 AC: 9438 AN: 10592

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61539 AN: 68014

Other (OTH) AF: 0.898 AC: 1900 AN: 2116

Alfa AF: 0.902 Hom.: 112816

Bravo AF: 0.884

Asia WGS AF: 0.842 AC: 2931 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.80
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs216298; hg19: chr12-6156477;