rs147680216
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2
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
NM_025216.3 missense
Scores
10
6
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 | P1 | |
WNT10A | ENST00000458582.1 | c.264-2530G>A | intron_variant | 3 | ENSP00000388812 |
Frequencies
GnomAD3 genomes AF: 0.000821 AC: 125AN: 152194Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00208 AC: 518AN: 249130Hom.: 12 AF XY: 0.00195 AC XY: 263AN XY: 135054
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GnomAD4 exome AF: 0.000586 AC: 857AN: 1461362Hom.: 18 Cov.: 32 AF XY: 0.000578 AC XY: 420AN XY: 727014
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GnomAD4 genome AF: 0.000827 AC: 126AN: 152312Hom.: 2 Cov.: 32 AF XY: 0.000953 AC XY: 71AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tooth agenesis, selective, 4 Pathogenic:1Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2014 | - - |
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. - |
Odonto-onycho-dermal dysplasia Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine | - | - - |
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. - |
Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at