rs147680216
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP3BP4_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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_025216.3
PP3
?
Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when 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. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High Homozygotes in GnomAd at 2 SD gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WNT10A | NM_025216.3 | c.637G>A | p.Gly213Ser | missense_variant | 3/4 | ENST00000258411.8 | |
WNT10A | XM_011511929.3 | c.541G>A | p.Gly181Ser | missense_variant | 4/5 | ||
WNT10A | XM_011511930.2 | c.377-2530G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WNT10A | ENST00000258411.8 | c.637G>A | p.Gly213Ser | missense_variant | 3/4 | 1 | NM_025216.3 | P1 | |
WNT10A | ENST00000458582.1 | c.264-2530G>A | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000821 AC: 125AN: 152194Hom.: 2 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
125
AN:
152194
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00208 AC: 518AN: 249130Hom.: 12 AF XY: 0.00195 AC XY: 263AN XY: 135054
GnomAD3 exomes
AF:
AC:
518
AN:
249130
Hom.:
AF XY:
AC XY:
263
AN XY:
135054
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000586 AC: 857AN: 1461362Hom.: 18 Cov.: 32 AF XY: 0.000578 AC XY: 420AN XY: 727014
GnomAD4 exome
AF:
AC:
857
AN:
1461362
Hom.:
Cov.:
32
AF XY:
AC XY:
420
AN XY:
727014
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000827 AC: 126AN: 152312Hom.: 2 Cov.: 32 AF XY: 0.000953 AC XY: 71AN XY: 74476
GnomAD4 genome
?
AF:
AC:
126
AN:
152312
Hom.:
Cov.:
32
AF XY:
AC XY:
71
AN XY:
74476
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
0
ExAC
?
AF:
AC:
208
Asia WGS
AF:
AC:
13
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain: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;C1835492:Tooth agenesis, selective, 4 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
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. - |
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 | Dec 20, 2022 | 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) - |
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
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at