rs216805

Variant names:

• chr12-6002310-A-G
• rs216805
• NM_000552.5:c.5843-6088T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-6002310-A-G
• chr12-6002310-A-T

Variant summary

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

The NM_000552.5(VWF):​c.5843-6088T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 151,644 control chromosomes in the GnomAD database, including 7,289 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 0.30 (7289 hom., cov: 32)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230
• 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 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.5843-6088T>C		intron_variant	Intron 34 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5843-6088T>C		intron_variant	Intron 34 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5843-6088T>C		intron_variant	Intron 34 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-8376T>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45027 AN: 151520 Hom.: 7268 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.297 AC: 45096 AN: 151644 Hom.: 7289 Cov.: 32 AF XY: 0.304 AC XY: 22523 AN XY: 74118

African (AFR) AF: 0.222 AC: 9196 AN: 41498

American (AMR) AF: 0.424 AC: 6463 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 898 AN: 3466

East Asian (EAS) AF: 0.495 AC: 2546 AN: 5142

South Asian (SAS) AF: 0.405 AC: 1942 AN: 4796

European-Finnish (FIN) AF: 0.290 AC: 3034 AN: 10452

Middle Eastern (MID) AF: 0.195 AC: 53 AN: 272

European-Non Finnish (NFE) AF: 0.296 AC: 20063 AN: 67762

Other (OTH) AF: 0.300 AC: 629 AN: 2094

Alfa AF: 0.172 Hom.: 376

Bravo AF: 0.304

Asia WGS AF: 0.430 AC: 1466 AN: 3408

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.8
DANN	Benign	0.55
PhyloP100		0.23
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: rs216805; hg19: chr12-6111476; COSMIC: COSV54612461;