rs147680216

Positions:

• chr2-218890244-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BS1_Supporting BS2

The NM_025216.3(WNT10A):​c.637G>A​(p.Gly213Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,613,674 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (18 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 B:4
• Conservation: PhyloP100: 9.84

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 Benign. Variant got -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.028582364).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000827 (126/152312) while in subpopulation EAS AF= 0.0235 (122/5184). AF 95% confidence interval is 0.0201. There are 2 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNT10A	NM_025216.3	c.637G>A	p.Gly213Ser	missense_variant	3/4	ENST00000258411.8	NP_079492.2
WNT10A	XM_011511929.3	c.541G>A	p.Gly181Ser	missense_variant	4/5		XP_011510231.1
WNT10A	XM_011511930.2	c.377-2530G>A		intron_variant			XP_011510232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT10A	ENST00000258411.8	c.637G>A	p.Gly213Ser	missense_variant	3/4	1	NM_025216.3	ENSP00000258411.3
WNT10A	ENST00000458582.1	c.263-2530G>A		intron_variant		3		ENSP00000388812.1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00208 AC: 518 AN: 249130 Hom.: 12 AF XY: 0.00195 AC XY: 263 AN XY: 135054

Gnomad AFR exome AF: 0.0000633

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0275

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000586 AC: 857 AN: 1461362 Hom.: 18 Cov.: 32 AF XY: 0.000578 AC XY: 420 AN XY: 727014

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0192

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152312 Hom.: 2 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74476

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000139 Hom.: 1

Bravo AF: 0.00105

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tooth agenesis, selective, 4 Pathogenic:1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine	-	- -

Odonto-onycho-dermal dysplasia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine	-	- -

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Tooth agenesis, selective, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Stomatology Center, Xiangya Hospital, Central South University

-

We used whole exome sequencing to compare tooth loss gene loci between two brothers with hypophidrotic ectodermal dysplasia (HED), analyze the difference of tooth loss phenotype, and explore its mechanism. wes showed that an EDA mutation was found in both older and younger brothers (c.878T>G), and the compound heterozygous mutation of WNT10A (c.511C>T and c.637G>A) Found only in the elder brothers. Prediction of secondary and tertiary structures of the WNT10A variants (p. R171C, p.G213S) indicated the impaired function of the molecule. The elder brothers have a more severe tooth loss phenotype than younger brothers. It has been reported that eda c.878T>G mutation caused HED (PMID: 30526585). We believe that EDA is the main pathogenic gene in the two patients, and the compound heterozygous WNT10A missense mutation can aggravate the HED phenotype caused by EDA mutation, resulting in a severe edentulous mandible phenotype in the elder brother. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34878701, 33932139, 31103801, 28944914, 31180159, 24312213, 30555066, 24449199, 29367877, 23401279, 24311251, 27657131, 29178643, 25629078, 34426522, 33034246, 24458874, 35537890, LiuH[article]2022, 36071541, 34834569, 34184264, 35546689, 33329022, 24043634, 36143186, 37228816, 37005710, 38163170, 36832485, 38280992) -

WNT10A-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

The WNT10A c.637G>A variant is predicted to result in the amino acid substitution p.Gly213Ser. This variant has been reported in the compound heterozygous state, with another variant in WNT10A (phase unknown), with variants in the EDA gene (phase unknown), and in the heterozygous state in individuals with mild ectodermal dysplasia or tooth agenesis (Patient 14, Plaisancié et al. 2013. PubMed ID: 23401279; Proband 52 and 53, He et al. 2013. PubMed ID: 2431221; Song et al. 2013. PubMed ID: 24043634; Family 1, Kantaputra et al. 2014. PubMed ID: 24311251; Yang et al. 2014. PubMed ID: 25629078; Yuan et al. 2017. PubMed ID: 29178643; Park et al. 2019. PubMed ID: 31103801). Of note, this variant has been reported in patients and in normal control populations (Song et al. 2013. PubMed ID: 24043634). Protein structure analysis predicted that this variant would alter protein structure (He et al. 2013. PubMed ID: 24312213). This variant is reported in 2.8% of alleles in individuals of East Asian descent in gnomAD including 14 homozygous individuals. This variant has conflicting interpretations in ClinVar ranging from likely pathogenic to uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/139576/). Taken together, we classify this variant as likely pathogenic. -

Tooth agenesis Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 15, 2014

- -

SchC6pf-Schulz-Passarge syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.97
MPC		0.43
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.96
gMVP		0.88

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: rs147680216; hg19: chr2-219754966;