12-6011912-C-T

Variant names:

• chr12-6011912-C-T
• rs216305
• NM_000552.5:c.5665-118G>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.5665-118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.486 in 1,147,626 control chromosomes in the GnomAD database, including 140,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26655 hom., cov: 30)
  • Exomes 𝑓: 0.47 (114155 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.372
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-6011912-C-T is Benign according to our data. Variant chr12-6011912-C-T is described in ClinVar as Benign. ClinVar VariationId is 1247093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.5665-118G>A		intron_variant	Intron 33 of 51	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5665-118G>A		intron_variant	Intron 33 of 51		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5665-118G>A		intron_variant	Intron 33 of 51	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-17978G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89079 AN: 151624 Hom.: 26634 Cov.: 30

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.601

GnomAD4 exome AF: 0.470 AC: 468258 AN: 995884 Hom.: 114155 Cov.: 15 AF XY: 0.479 AC XY: 245800 AN XY: 513068

African (AFR) AF: 0.643 AC: 13988 AN: 21768

American (AMR) AF: 0.671 AC: 27882 AN: 41526

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 13602 AN: 21986

East Asian (EAS) AF: 0.634 AC: 23504 AN: 37090

South Asian (SAS) AF: 0.593 AC: 43473 AN: 73344

European-Finnish (FIN) AF: 0.456 AC: 24015 AN: 52696

Middle Eastern (MID) AF: 0.654 AC: 2930 AN: 4482

European-Non Finnish (NFE) AF: 0.424 AC: 296174 AN: 698506

Other (OTH) AF: 0.510 AC: 22690 AN: 44486

GnomAD4 genome AF: 0.587 AC: 89140 AN: 151742 Hom.: 26655 Cov.: 30 AF XY: 0.590 AC XY: 43758 AN XY: 74150

African (AFR) AF: 0.689 AC: 28515 AN: 41362

American (AMR) AF: 0.648 AC: 9891 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2211 AN: 3468

East Asian (EAS) AF: 0.645 AC: 3311 AN: 5136

South Asian (SAS) AF: 0.629 AC: 3018 AN: 4798

European-Finnish (FIN) AF: 0.461 AC: 4851 AN: 10522

Middle Eastern (MID) AF: 0.695 AC: 203 AN: 292

European-Non Finnish (NFE) AF: 0.522 AC: 35402 AN: 67880

Other (OTH) AF: 0.599 AC: 1262 AN: 2108

Alfa AF: 0.556 Hom.: 2930

Bravo AF: 0.606

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

- -

Nov 12, 2018

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	-0.92
CADD	Benign	1.8
DANN	Benign	0.33
PhyloP100		-0.37
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: rs216305; hg19: chr12-6121078; COSMIC: COSV107218075;