NM_000552.5:c.1946-903A>G

Variant names:

• chr12-6053686-T-C
• rs2283333
• NM_000552.5:c.1946-903A>G

Variant summary

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

The NM_000552.5(VWF):​c.1946-903A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 152,256 control chromosomes in the GnomAD database, including 59,620 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 (59620 hom., cov: 33)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.974
• Publications: 10 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 = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.1946-903A>G		intron_variant	Intron 15 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1946-903A>G		intron_variant	Intron 15 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1946-903A>G		intron_variant	Intron 15 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+56829A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.884 AC: 134540 AN: 152138 Hom.: 59593 Cov.: 33

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.886

Gnomad OTH AF: 0.902

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

GnomAD4 genome AF: 0.884 AC: 134614 AN: 152256 Hom.: 59620 Cov.: 33 AF XY: 0.884 AC XY: 65780 AN XY: 74446

African (AFR) AF: 0.893 AC: 37073 AN: 41538

American (AMR) AF: 0.899 AC: 13750 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3193 AN: 3470

East Asian (EAS) AF: 0.782 AC: 4042 AN: 5172

South Asian (SAS) AF: 0.866 AC: 4179 AN: 4824

European-Finnish (FIN) AF: 0.857 AC: 9093 AN: 10614

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.886 AC: 60288 AN: 68016

Other (OTH) AF: 0.898 AC: 1898 AN: 2114

Alfa AF: 0.883 Hom.: 64568

Bravo AF: 0.889

Asia WGS AF: 0.830 AC: 2887 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	1.9
DANN	Benign	0.53
PhyloP100		-0.97
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: rs2283333; hg19: chr12-6162852;