rs318240759

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_025216.3(WNT10A):​c.283G>A​(p.Glu95Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

WNT10A
NM_025216.3 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:2O:1

Conservation

PhyloP100: 9.51
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 Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952
PP5
Variant 2-218882330-G-A is Pathogenic according to our data. Variant chr2-218882330-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218882330-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNT10ANM_025216.3 linkc.283G>A p.Glu95Lys missense_variant 2/4 ENST00000258411.8 NP_079492.2 Q9GZT5A0A2K8FR47
WNT10AXM_011511929.3 linkc.187G>A p.Glu63Lys missense_variant 3/5 XP_011510231.1
WNT10AXM_011511930.2 linkc.283G>A p.Glu95Lys missense_variant 2/3 XP_011510232.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNT10AENST00000258411.8 linkc.283G>A p.Glu95Lys missense_variant 2/41 NM_025216.3 ENSP00000258411.3 Q9GZT5
WNT10AENST00000458582.1 linkc.169G>A p.Glu57Lys missense_variant 1/23 ENSP00000388812.1 H7BZB8

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152100
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251452
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152100
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000271
Hom.:
0
Bravo
AF:
0.0000302
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxApr 29, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23401279, 22581971, 37361548) -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 95 of the WNT10A protein (p.Glu95Lys). This variant is present in population databases (rs318240759, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive WNT10A-related conditions (PMID: 22581971, 23401279; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WNT10A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Tooth agenesis, selective, 4 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2012- -
SchC6pf-Schulz-Passarge syndrome Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
WNT10A-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 02, 2023The WNT10A c.283G>A variant is predicted to result in the amino acid substitution p.Glu95Lys. This variant has been reported in the compound heterozygous and homozygous states in individuals with isolated tooth agenesis or with clinical features of ectodermal dysplasia (Proband 8, van den Boogaard et al. 2012. PubMed ID: 22581971; Patient 11, Plaisancié et al. 2013. PubMed ID: 23401279). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219747052-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D
Eigen
Pathogenic
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-3.3
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MVP
0.95
MPC
0.45
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.96
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs318240759; hg19: chr2-219747052; COSMIC: COSV51462536; COSMIC: COSV51462536; API