chr12-6016654-G-A

Position:

• chr12-6016654-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.5173C>T is a missense variant that replaces proline with serine at position 1725. TThe Grpmax filtering allele frequency in gnomAD v4.1 is 0.02354 (based on 1836/75022 alleles in the African / African-American population, with 27 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 for BS1. While this variant has been reported in healthy control individuals (PMID:22197721), BS2 is not being used due to penetrance issues. In summary, this variant meets the criteria to be classified as Likely Benign for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402355/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0073 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (13 hom.)
• Consequence: VWF NM_000552.5 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.76

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 Likely_benign. Variant got -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.5173C>T	p.Pro1725Ser	missense_variant, splice_region_variant	30/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.5173C>T	p.Pro1725Ser	missense_variant, splice_region_variant	30/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.5173C>T	p.Pro1725Ser	missense_variant, splice_region_variant	30/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-22720C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00731 AC: 1112 AN: 152174 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00198 AC: 498 AN: 251492 Hom.: 12 AF XY: 0.00149 AC XY: 203 AN XY: 135920

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000746 AC: 1091 AN: 1461892 Hom.: 13 Cov.: 32 AF XY: 0.000653 AC XY: 475 AN XY: 727246

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00731 AC: 1113 AN: 152292 Hom.: 16 Cov.: 32 AF XY: 0.00716 AC XY: 533 AN XY: 74480

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00160 Hom.: 6

Bravo AF: 0.00868

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00230 AC: 279

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 15, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.056
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.35
Sift	Benign	0.28	T
Sift4G	Benign	0.094	T
Polyphen		0.15	B
Vest4		0.42
MVP		0.82
MPC		0.92
ClinPred		0.017	T
GERP RS		3.4
Varity_R		0.29
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs78302129; hg19: chr12-6125820;