chr12-6022793-G-A

Position:

• chr12-6022793-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BA1

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.3485C>T is a missense variant that replaces proline with leucine at position 1162. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.2036 (based on 7087/34136 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.1) for BA1, and therefore meets this criterion (BA1). Heterologous expression of the variant protein revealed similarities to the wild-type VWF control in secretion, collagen binding, GPIb binding, and multimerization (PMID:28544236). The computational predictor REVEL gives a score of 0.677, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402756/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.054 (530 hom., cov: 11)
  • Exomes 𝑓: 0.0082 (275 hom.)
  • Failed GnomAD Quality Control
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.35

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 -7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.3485C>T	p.Pro1162Leu	missense_variant	26/52	ENST00000261405.10
VWF	XM_047429501.1	c.3485C>T	p.Pro1162Leu	missense_variant	26/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.3485C>T	p.Pro1162Leu	missense_variant	26/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-28859C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 4858 AN: 90098 Hom.: 528 Cov.: 11

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000805

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0182

Gnomad NFE AF: 0.000973

Gnomad OTH AF: 0.0644

GnomAD3 exomes AF: 0.0256 AC: 1391 AN: 54328 Hom.: 125 AF XY: 0.0228 AC XY: 624 AN XY: 27388

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00989

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00824 AC: 3629 AN: 440470 Hom.: 275 Cov.: 0 AF XY: 0.00701 AC XY: 1628 AN XY: 232400

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000489

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000899

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0540 AC: 4870 AN: 90138 Hom.: 530 Cov.: 11 AF XY: 0.0542 AC XY: 2167 AN XY: 39996

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.0300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000807

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000974

Gnomad4 OTH AF: 0.0638

Alfa AF: 0.0514 Hom.: 65

ExAC AF: 0.00375 AC: 21

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

research

Laboratory of Hematology, Radboud University Medical Center

Dec 10, 2020

- -

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
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0019	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	3.0e-11	P
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.94
ClinPred		0.028	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.58

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: rs566672558; hg19: chr12-6131959;