12-5993736-C-T

Variant names:

• chr12-5993736-C-T
• rs216900
• NM_000552.5:c.6598+126G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.6598+126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 806,516 control chromosomes in the GnomAD database, including 2,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (453 hom., cov: 30)
  • Exomes 𝑓: 0.081 (2511 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.412
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-5993736-C-T is Benign according to our data. Variant chr12-5993736-C-T is described in ClinVar as Benign. ClinVar VariationId is 1250723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.6598+126G>A		intron_variant	Intron 37 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6598+126G>A		intron_variant	Intron 37 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6598+126G>A		intron_variant	Intron 37 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.*144G>A		downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9732 AN: 150858 Hom.: 453 Cov.: 30

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.00234

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0490

GnomAD4 exome AF: 0.0808 AC: 52966 AN: 655542 Hom.: 2511 AF XY: 0.0803 AC XY: 27842 AN XY: 346830

African (AFR) AF: 0.0129 AC: 224 AN: 17318

American (AMR) AF: 0.0833 AC: 2752 AN: 33024

Ashkenazi Jewish (ASJ) AF: 0.0448 AC: 863 AN: 19254

East Asian (EAS) AF: 0.000553 AC: 18 AN: 32528

South Asian (SAS) AF: 0.0563 AC: 3445 AN: 61138

European-Finnish (FIN) AF: 0.132 AC: 4309 AN: 32666

Middle Eastern (MID) AF: 0.0347 AC: 97 AN: 2794

European-Non Finnish (NFE) AF: 0.0921 AC: 38962 AN: 423102

Other (OTH) AF: 0.0681 AC: 2296 AN: 33718

GnomAD4 genome AF: 0.0645 AC: 9734 AN: 150974 Hom.: 453 Cov.: 30 AF XY: 0.0643 AC XY: 4736 AN XY: 73686

African (AFR) AF: 0.0166 AC: 681 AN: 41042

American (AMR) AF: 0.0652 AC: 988 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3466

East Asian (EAS) AF: 0.00234 AC: 12 AN: 5120

South Asian (SAS) AF: 0.0530 AC: 253 AN: 4770

European-Finnish (FIN) AF: 0.116 AC: 1197 AN: 10330

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0917 AC: 6218 AN: 67802

Other (OTH) AF: 0.0485 AC: 101 AN: 2082

Alfa AF: 0.0875 Hom.: 105

Bravo AF: 0.0571

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.68
PhyloP100		-0.41
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: rs216900; hg19: chr12-6102902;