rs121908119

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting

The NM_025216.3(WNT10A):c.321C>A(p.Cys107*) 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 benign 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:32O:2

Conservation

PhyloP100: 3.06

Publications

36 publications found

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 Gene-Disease associations (from GenCC):

ectodermal dysplasia WNT10A related
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
tooth agenesis, selective, 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
odonto-onycho-dermal dysplasia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Schöpf-Schulz-Passarge syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hypohidrotic ectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WNT10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PVS1

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

PP5

Variant 2-218882368-C-A is Pathogenic according to our data. Variant chr2-218882368-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00147 (2147/1461878) while in subpopulation NFE AF = 0.00189 (2099/1112002). AF 95% confidence interval is 0.00182. There are 1 homozygotes in GnomAdExome4. There are 1008 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT10A	NM_025216.3 link	c.321C>A	p.Cys107*	stop_gained	Exon 2 of 4	ENST00000258411.8	NP_079492.2	Q9GZT5A0A2K8FR47
WNT10A	XM_011511929.3 link	c.225C>A	p.Cys75*	stop_gained	Exon 3 of 5		XP_011510231.1
WNT10A	XM_011511930.2 link	c.321C>A	p.Cys107*	stop_gained	Exon 2 of 3		XP_011510232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT10A	ENST00000258411.8 link	c.321C>A	p.Cys107*	stop_gained	Exon 2 of 4	1	NM_025216.3	ENSP00000258411.3		Q9GZT5
WNT10A	ENST00000458582.1 link	c.207C>A	p.Cys69*	stop_gained	Exon 1 of 2	3		ENSP00000388812.1		H7BZB8

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

GnomAD2 exomes

AF:

0.000621

AC:

156

AN:

251318

AF XY:

0.000633

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 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

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00189

AC:

2099

AN:

1112002

Other (OTH)

AF:

0.000580

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

129

259

388

518

647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000834

AC:

127

AN:

152318

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41572

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00100

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:32Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 25, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 17, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 17, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

WNT10A: PM3:Very Strong, PVS1, PP1:Strong, PM2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tooth agenesis, selective, 4

Pathogenic:7

Dec 07, 2021

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with odontoonychodermal dysplasia (MIM#257980), Schopf-Schulz-Passarge syndrome (MIM#224750) and selective tooth agenesis 4 (MIM#150400). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). There is a high degree of variability in phenotypic expression, however generally dominant inheritance results in a milder phenotype (PMID: 19559398, PMID: 30426266). (I) 0112 - The condition associated with this gene has incomplete penetrance. Heterozygous carriers may be asymptomatic (OMIM, PMID: 19559398; 30426266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (181 heterozygotes, 0 homozygotes). (SP) 0702 - Other NMD predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (Decipher, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported pathogenic in multiple unrelated homozygous, compound heterozygous and heterozygous individuals with ectodermal dysplasia or non-syndromic oligodontia (ClinVar, PMID: 19559398, PMID:30426266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 21, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 04, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 02, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM3_Strong -

WNT10A-related disorder

Pathogenic:3

Mar 22, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS3_Supporting, PM1, PM3_Very Strong, PP1 -

Oct 31, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Pathogenic:3

Mar 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: WNT10A c.321C>A (p.Cys107X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00062 in 251318 control chromosomes (gnomAD). c.321C>A has been reported in the literature in multiple individuals affected with ectodermal dysplasia (example: Bohring_2009). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 19559398). ClinVar contains an entry for this variant (Variation ID: 4461). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Institute of Human Genetics, University Hospital of Duesseldorf

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Pathogenic:2Other:1

Aug 13, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Schöpf-Schulz-Passarge syndrome

Pathogenic:2

May 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ectodermal dysplasia

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 16, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Pathogenic:1

Mar 30, 2023

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 04, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.321C>A (p.C107*) alteration, located in coding exon 2 of the WNT10A gene, consists of a C to A substitution at nucleotide position 321. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 107. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.064% (181/282692) total alleles studied. The highest observed frequency was 0.129% (167/129028) of European (non-Finnish) alleles. The c.321C>A (p.C107*) alteration has been reported in multiple unrelated affected individuals with tooth agenesis with ectodermal symptoms or odonto-onycho-dermal dysplasia (Bohring, 2009; Mostowska, 2013; Clauss, 2014; Bergendal, 2016; Farwell, 2015). Some heterozygous carriers of this alteration have been reported with dental features that are more mild compared to individuals with bilallelic WNT10A alterations (Mostowska, 2013; Vink, 2014; Yang, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

PhyloP100

3.1

Vest4

0.88

ClinPred

0.23

GERP RS

2.9

PromoterAI

-0.0026

Neutral

(source)

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over