rs216873

Variant names:

• chr12-5986108-T-C
• rs216873
• NM_000552.5:c.6799-443A>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.6799-443A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 152,052 control chromosomes in the GnomAD database, including 43,362 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. The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.75 (43362 hom., cov: 31)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 9 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 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.6799-443A>G		intron	N/A	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.6799-443A>G		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.6799-443A>G		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2968-32514A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114213 AN: 151936 Hom.: 43319 Cov.: 31

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.769

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

GnomAD4 genome AF: 0.752 AC: 114308 AN: 152052 Hom.: 43362 Cov.: 31 AF XY: 0.751 AC XY: 55795 AN XY: 74318

African (AFR) AF: 0.649 AC: 26915 AN: 41452

American (AMR) AF: 0.814 AC: 12445 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2862 AN: 3466

East Asian (EAS) AF: 0.673 AC: 3471 AN: 5160

South Asian (SAS) AF: 0.672 AC: 3237 AN: 4816

European-Finnish (FIN) AF: 0.793 AC: 8393 AN: 10590

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.801 AC: 54461 AN: 67968

Other (OTH) AF: 0.770 AC: 1622 AN: 2106

Alfa AF: 0.789 Hom.: 171919

Bravo AF: 0.752

Asia WGS AF: 0.699 AC: 2434 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.29
DANN	Benign	0.61
PhyloP100		-1.3
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: rs216873; hg19: chr12-6095274;