12-6025065-C-G

Variant names:

• chr12-6025065-C-G
• rs11609815
• NM_000552.5:c.3222+515G>C

Variant summary

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

The NM_000552.5(VWF):​c.3222+515G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 150,570 control chromosomes in the GnomAD database, including 6,787 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 0.28 (6787 hom., cov: 31)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786
• 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 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.3222+515G>C		intron_variant	Intron 24 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3222+515G>C		intron_variant	Intron 24 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3222+515G>C		intron_variant	Intron 24 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-31131G>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42445 AN: 150498 Hom.: 6773 Cov.: 31

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.262

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

GnomAD4 genome AF: 0.282 AC: 42495 AN: 150570 Hom.: 6787 Cov.: 31 AF XY: 0.274 AC XY: 20138 AN XY: 73392

African (AFR) AF: 0.425 AC: 17398 AN: 40934

American (AMR) AF: 0.207 AC: 3146 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3466

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5146

South Asian (SAS) AF: 0.111 AC: 529 AN: 4762

European-Finnish (FIN) AF: 0.248 AC: 2480 AN: 9980

Middle Eastern (MID) AF: 0.194 AC: 56 AN: 288

European-Non Finnish (NFE) AF: 0.255 AC: 17298 AN: 67836

Other (OTH) AF: 0.261 AC: 541 AN: 2074

Alfa AF: 0.141 Hom.: 249

Bravo AF: 0.288

Asia WGS AF: 0.0790 AC: 279 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.40
PhyloP100		-0.79
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: rs11609815; hg19: chr12-6134231;