rs121908119

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025216.3(WNT10A):c.321C>A(p.Cys107Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 1 hom. )

Consequence

WNT10A
NM_025216.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:2

Conservation

PhyloP100: 3.06

Variant links:

Genes affected

WNT10A (HGNC:13829): (Wnt family member 10A) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It is strongly expressed in the cell lines of promyelocytic leukemia and Burkitt's lymphoma. In addition, it and another family member, the WNT6 gene, are strongly coexpressed in colorectal cancer cell lines. The gene overexpression may play key roles in carcinogenesis through activation of the WNT-beta-catenin-TCF signaling pathway. This gene and the WNT6 gene are clustered in the chromosome 2q35 region. [provided by RefSeq, Jul 2008]

WNT10A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-218882368-C-A is Pathogenic according to our data. Variant chr2-218882368-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218882368-C-A is described in Lovd as [Pathogenic]. Variant chr2-218882368-C-A is described in Lovd as [Pathogenic]. Variant chr2-218882368-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-218882368-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
WNT10A	NM_025216.3 linkuse as main transcript	c.321C>A	p.Cys107Ter	stop_gained	2/4	ENST00000258411.8
WNT10A	XM_011511929.3 linkuse as main transcript	c.225C>A	p.Cys75Ter	stop_gained	3/5
WNT10A	XM_011511930.2 linkuse as main transcript	c.321C>A	p.Cys107Ter	stop_gained	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10A	ENST00000258411.8 linkuse as main transcript	c.321C>A	p.Cys107Ter	stop_gained	2/4	1	NM_025216.3	P1
WNT10A	ENST00000458582.1 linkuse as main transcript	c.210C>A	p.Cys70Ter	stop_gained	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.000834

AC:

127

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000621

AC:

156

AN:

251318

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00147

AC:

2147

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1008

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00189

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152318

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00160

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000997

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00136

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	WNT10A: PM3:Very Strong, PVS1, PP1:Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2021	One of the most common pathogenic variants reported in the WNT10A gene (Vink et al., 2014) Observed in the homozygous state or in trans with a second pathogenic variant in individuals with either isolated oligodontia or other features of ectodermal dysplasia (Bohring et al., 2009; Cluzeau et al., 2011; Plaisancie et al., 2013; Mostowska et al., 2013; Clauss et al., 2014; Tardieu et al., 2017) Identified in the heterozygous state in individuals with isolated hypodontia or oligodontia, individuals with features of ectodermal dysplasia, and unaffected carriers (Bohring et al., 2009; Cluzeau et al., 2011; van den Boogaard et al., 2012; Mostowska et al., 2013) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease Observed in 0.064% (181/282692 alleles) in large population cohorts (Lek et al., 2016) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jun 25, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2022	- -

Tooth agenesis, selective, 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.321C>A;p.(Cys107) variant creates a premature translational stop signal in the WNT10A gene. It is expected to result in an absent or disrupted protein product -PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 4461; PMID: 28105635; 26964878; 25629078; 25545742; 24902757; 24449199; 19559398; 21279306) - PS4. The p.(Cys107) was detected in trans with a pathogenic variant (PMID: 28105635; PMID: 26964878; 25629078; 24902757; 19559398; 21279306) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 26964878; 25629078; 19559398; 21279306) - PP1_strong and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 21, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 04, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Dec 07, 2021	- -

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4;C1857069:SchC6pf-Schulz-Passarge syndrome

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Aug 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 10-03-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

SchC6pf-Schulz-Passarge syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Mar 30, 2023

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -

WNT10A-Related Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 31, 2018

The WNT10A c.321C>A (p.Cys107Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature involving probands with WNT10A-related disorders consisting of a spectrum of phenotypes including odontoonychodermal dysplasia, Schopf-Schulz-Passarge syndrome and selective tooth agenesis, the variant was found in a homozygous state in 12 individuals, in a compound heterozygous state in a total of 30 individuals, and in 29 symptomatic heterozygous individuals (Bohring et al. 2009; Petrof et al. 2011; Van den Boogaard et al. 2012; Mostowska et al. 2013; Clauss et al. 2014; Tziotzios et al. 2014; Vink et al. 2014; Arzoo et al. 2014). The variant was absent from 800 control subjects but is reported at a frequency of 0.00140 in the European American population of the Exome Sequencing Project. Due to the potential impact of stop-gained variants and available evidence, the p.Cys107Ter variant is classified as pathogenic for WNT10A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

WNT10A-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

The WNT10A c.321C>A variant is predicted to result in premature protein termination (p.Cys107*). This variant has been reported in the compound heterozygous and homozygous states to be pathogenic for ectodermal dysplasia (Bohring et al. 2009. PubMed ID: 19559398; Vink et al. 2014. PubMed ID: 24398796; Guazzarotti et al. 2018. PubMed ID: 28976000). This variant has also been reported in the heterozygous state to be pathogenic for abnormal tooth shape and tooth number (Vink et al. 2014. PubMed ID: 24398796). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in WNT10A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change creates a premature translational stop signal (p.Cys107*) in the WNT10A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WNT10A are known to be pathogenic (PMID: 17847007, 22581971, 25629078). This variant is present in population databases (rs121908119, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with odonto-onycho-dermal dysplasia, Schopf-Schultz-Passarge syndrome, and isolated tooth agenesis (PMID: 19559398, 23167694, 24398796, 25545742, 25629078). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4461). For these reasons, this variant has been classified as Pathogenic. -

Odonto-onycho-dermal dysplasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2012

- -

Ectodermal dysplasia

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

Vest4

0.88

ClinPred

0.23

GERP RS

2.9

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over