rs147680216

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

Scores

10
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4B:4

Conservation

PhyloP100: 9.84
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]

Genome browser will be placed here

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
WNT10ANM_025216.3 linkuse as main transcriptc.637G>A p.Gly213Ser missense_variant 3/4 ENST00000258411.8 NP_079492.2
WNT10AXM_011511929.3 linkuse as main transcriptc.541G>A p.Gly181Ser missense_variant 4/5 XP_011510231.1
WNT10AXM_011511930.2 linkuse as main transcriptc.377-2530G>A intron_variant XP_011510232.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNT10AENST00000258411.8 linkuse as main transcriptc.637G>A p.Gly213Ser missense_variant 3/41 NM_025216.3 ENSP00000258411 P1
WNT10AENST00000458582.1 linkuse as main transcriptc.264-2530G>A intron_variant 3 ENSP00000388812

Frequencies

GnomAD3 genomes
AF:
0.000821
AC:
125
AN:
152194
Hom.:
2
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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: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 providedclinical testingDepartment of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2014- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 providedclinical testingDepartment of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine-- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Tooth agenesis, selective, 2 Pathogenic:1
Pathogenic, criteria provided, single submitterresearchStomatology 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 submitterclinical testingGeneDxJul 11, 2024In 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 providedclinical testingPreventionGenetics, part of Exact SciencesMar 19, 2024The 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 providedliterature onlyYale Center for Mendelian Genomics, Yale UniversitySep 15, 2014- -
SchC6pf-Schulz-Passarge syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
MutationTaster
Benign
1.0
D
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

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

Other links and lift over

dbSNP: rs147680216; hg19: chr2-219754966; API