12-5990683-C-G

Variant names:

• chr12-5990683-C-G
• rs216891
• NM_000552.5:c.6798+1136G>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.6798+1136G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 151,388 control chromosomes in the GnomAD database, including 19,394 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 0.50 (19394 hom., cov: 27)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• 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 = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.6798+1136G>C		intron_variant	Intron 38 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6798+1136G>C		intron_variant	Intron 38 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6798+1136G>C		intron_variant	Intron 38 of 51	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75166 AN: 151268 Hom.: 19378 Cov.: 27

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.497 AC: 75217 AN: 151388 Hom.: 19394 Cov.: 27 AF XY: 0.500 AC XY: 36994 AN XY: 73918

African (AFR) AF: 0.371 AC: 15252 AN: 41164

American (AMR) AF: 0.566 AC: 8625 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1669 AN: 3468

East Asian (EAS) AF: 0.747 AC: 3840 AN: 5138

South Asian (SAS) AF: 0.594 AC: 2828 AN: 4762

European-Finnish (FIN) AF: 0.503 AC: 5268 AN: 10464

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36108 AN: 67858

Other (OTH) AF: 0.502 AC: 1050 AN: 2092

Alfa AF: 0.507 Hom.: 2414

Bravo AF: 0.492

Asia WGS AF: 0.620 AC: 2158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.24
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs216891; hg19: chr12-6099849;