rs216295

Variant names:

• chr12-6045040-T-C
• rs216295
• NM_000552.5:c.2282-589A>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.2282-589A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.874 in 152,170 control chromosomes in the GnomAD database, including 58,351 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 0.87 (58351 hom., cov: 32)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.732
• Publications: 3 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: Orphanet, ClinGen
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.898 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.2282-589A>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.2282-589A>G		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2282-589A>G		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2282-589A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132967 AN: 152052 Hom.: 58320 Cov.: 32

Gnomad AFR AF: 0.812

Gnomad AMI AF: 0.923

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.890

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.901

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

GnomAD4 genome AF: 0.874 AC: 133055 AN: 152170 Hom.: 58351 Cov.: 32 AF XY: 0.875 AC XY: 65095 AN XY: 74398

African (AFR) AF: 0.812 AC: 33679 AN: 41484

American (AMR) AF: 0.906 AC: 13858 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3254 AN: 3470

East Asian (EAS) AF: 0.784 AC: 4060 AN: 5178

South Asian (SAS) AF: 0.890 AC: 4283 AN: 4812

European-Finnish (FIN) AF: 0.891 AC: 9437 AN: 10596

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

European-Non Finnish (NFE) AF: 0.904 AC: 61483 AN: 68016

Other (OTH) AF: 0.895 AC: 1893 AN: 2114

Alfa AF: 0.886 Hom.: 26900

Bravo AF: 0.874

Asia WGS AF: 0.840 AC: 2922 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.56
PhyloP100		-0.73
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs216295;

hg19: chr12-6154206;