rs216901

Variant names:

• chr12-5995702-G-A
• rs216901
• NM_000552.5:c.6063+300C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000552.5(VWF):​c.6063+300C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 152,000 control chromosomes in the GnomAD database, including 20,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.52 (20711 hom., cov: 31)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.191
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-5995702-G-A is Benign according to our data. Variant chr12-5995702-G-A is described in ClinVar as Benign. ClinVar VariationId is 1182188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.728 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.6063+300C>T		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.6063+300C>T		intron	N/A	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.6063+300C>T		intron	N/A	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+33640C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78534 AN: 151882 Hom.: 20690 Cov.: 31

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.413

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.514

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

GnomAD4 genome AF: 0.517 AC: 78592 AN: 152000 Hom.: 20711 Cov.: 31 AF XY: 0.520 AC XY: 38637 AN XY: 74292

African (AFR) AF: 0.443 AC: 18375 AN: 41450

American (AMR) AF: 0.576 AC: 8806 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3468

East Asian (EAS) AF: 0.747 AC: 3861 AN: 5166

South Asian (SAS) AF: 0.593 AC: 2853 AN: 4812

European-Finnish (FIN) AF: 0.500 AC: 5272 AN: 10542

Middle Eastern (MID) AF: 0.410 AC: 119 AN: 290

European-Non Finnish (NFE) AF: 0.531 AC: 36106 AN: 67970

Other (OTH) AF: 0.517 AC: 1089 AN: 2108

Alfa AF: 0.523 Hom.: 2712

Bravo AF: 0.516

Asia WGS AF: 0.620 AC: 2157 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.56
PhyloP100		0.19
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: rs216901; hg19: chr12-6104868;