rs216312

Positions:

• chr12-6019818-T-C

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.3675-75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,486,220 control chromosomes in the GnomAD database, including 243,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30433 hom., cov: 32)
  • Exomes 𝑓: 0.56 (212972 hom.)
• Consequence: VWF NM_000552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.100

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 12-6019818-T-C is Benign according to our data. Variant chr12-6019818-T-C is described in ClinVar as [Benign]. Clinvar id is 1241069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019818-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3675-75A>G		intron_variant		ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3675-75A>G		intron_variant			XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3675-75A>G		intron_variant		1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-25884A>G		intron_variant		4
VWF	ENST00000539641.1	n.473-75A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94775 AN: 151912 Hom.: 30387 Cov.: 32

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.562 AC: 750239 AN: 1334190 Hom.: 212972 AF XY: 0.562 AC XY: 372277 AN XY: 662154

Gnomad4 AFR exome AF: 0.773

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.638

Gnomad4 EAS exome AF: 0.625

Gnomad4 SAS exome AF: 0.585

Gnomad4 FIN exome AF: 0.477

Gnomad4 NFE exome AF: 0.546

Gnomad4 OTH exome AF: 0.585

GnomAD4 genome AF: 0.624 AC: 94876 AN: 152030 Hom.: 30433 Cov.: 32 AF XY: 0.624 AC XY: 46340 AN XY: 74310

Gnomad4 AFR AF: 0.763

Gnomad4 AMR AF: 0.683

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.631

Gnomad4 SAS AF: 0.599

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.549

Gnomad4 OTH AF: 0.632

Alfa AF: 0.577 Hom.: 38125

Bravo AF: 0.648

Asia WGS AF: 0.650 AC: 2258 AN: 3478

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	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.7
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs216312; hg19: chr12-6128984;