rs121908119

Positions:

• chr2-218882368-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

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 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 O:2
• Conservation: PhyloP100: 3.06

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]

ACMG classification

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	Protein	UniProt
WNT10A	NM_025216.3	c.321C>A	p.Cys107*	stop_gained	2/4	ENST00000258411.8	NP_079492.2
WNT10A	XM_011511929.3	c.225C>A	p.Cys75*	stop_gained	3/5		XP_011510231.1
WNT10A	XM_011511930.2	c.321C>A	p.Cys107*	stop_gained	2/3		XP_011510232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT10A	ENST00000258411.8	c.321C>A	p.Cys107*	stop_gained	2/4	1	NM_025216.3	ENSP00000258411.3
WNT10A	ENST00000458582.1	c.207C>A	p.Cys69*	stop_gained	1/2	3		ENSP00000388812.1

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152200 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000633 AC XY: 86 AN XY: 135860

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.: 1 Cov.: 32 AF XY: 0.00139 AC XY: 1008 AN XY: 727244

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.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74488

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.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000585 AC: 71

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00136

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jun 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	WNT10A: PM3:Very Strong, PVS1, PP1:Strong, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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) -

Tooth agenesis, selective, 4 Pathogenic:7

Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Dec 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 21, 2021	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 02, 2024	PVS1, PM3_Strong -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -

WNT10A-related disorder Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 30, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 22, 2024	PVS1, PS3_Supporting, PM1, PM3_Very Strong, PP1 -
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. -

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4;C1857069:SchC6pf-Schulz-Passarge syndrome Pathogenic:2 Other:1

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Aug 13, 2016	- -

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	- -

Odonto-onycho-dermal dysplasia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2024	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. -

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

Nov 04, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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. -

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	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.88
ClinPred		0.23	T
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

Other links and lift over

dbSNP: rs121908119; hg19: chr2-219747090;