rs56981471

Positions:

• chr12-6011792-G-A
• chr12-6011792-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.5667C>T​(p.Pro1889=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,609,390 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1889P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (76 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (89 hom.)
• Consequence: VWF NM_000552.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0420

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-6011792-G-A is Benign according to our data. Variant chr12-6011792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6011792-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.042 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.5667C>T	p.Pro1889=	splice_region_variant, synonymous_variant	34/52	ENST00000261405.10
VWF	XM_047429501.1	c.5667C>T	p.Pro1889=	splice_region_variant, synonymous_variant	34/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.5667C>T	p.Pro1889=	splice_region_variant, synonymous_variant	34/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-17858C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2963 AN: 151846 Hom.: 77 Cov.: 31

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00958

Gnomad ASJ AF: 0.00693

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00531 AC: 1231 AN: 231986 Hom.: 29 AF XY: 0.00409 AC XY: 517 AN XY: 126550

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000867

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00255 AC: 3722 AN: 1457426 Hom.: 89 Cov.: 29 AF XY: 0.00224 AC XY: 1627 AN XY: 725284

Gnomad4 AFR exome AF: 0.0697

Gnomad4 AMR exome AF: 0.00453

Gnomad4 ASJ exome AF: 0.00572

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000500

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000578

Gnomad4 OTH exome AF: 0.00513

GnomAD4 genome AF: 0.0195 AC: 2965 AN: 151964 Hom.: 76 Cov.: 31 AF XY: 0.0187 AC XY: 1388 AN XY: 74250

Gnomad4 AFR AF: 0.0651

Gnomad4 AMR AF: 0.00956

Gnomad4 ASJ AF: 0.00693

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000986

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00369 Hom.: 10

Bravo AF: 0.0226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 09, 2022

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.7
DANN	Benign	0.83

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: rs56981471; hg19: chr12-6120958; COSMIC: COSV54628341;