chr12-6011912-C-T

Position:

• chr12-6011912-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1247093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6011912-C-T is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.5665-118G>A		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5665-118G>A		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5665-118G>A		intron_variant		1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-17978G>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR exome AF: 0.643

Gnomad4 AMR exome AF: 0.671

Gnomad4 ASJ exome AF: 0.619

Gnomad4 EAS exome AF: 0.634

Gnomad4 SAS exome AF: 0.593

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.424

Gnomad4 OTH exome AF: 0.510

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

Gnomad4 AFR AF: 0.689

Gnomad4 AMR AF: 0.648

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.645

Gnomad4 SAS AF: 0.629

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.522

Gnomad4 OTH AF: 0.599

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs216305; hg19: chr12-6121078;