rs1553623335

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_025216.3(WNT10A):c.1034T>C(p.Phe345Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,444,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F345L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

WNT10A
NM_025216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 4.00

Publications

1 publications found

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]

WNT10A Gene-Disease associations (from GenCC):

ectodermal dysplasia WNT10A related
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
tooth agenesis, selective, 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
odonto-onycho-dermal dysplasia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Schöpf-Schulz-Passarge syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tooth agenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hypohidrotic ectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WNT10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

PP5

Variant 2-218893051-T-C is Pathogenic according to our data. Variant chr2-218893051-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464178.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
WNT10A	NM_025216.3 link	c.1034T>C	p.Phe345Ser	missense_variant	Exon 4 of 4	ENST00000258411.8	NP_079492.2
WNT10A	XM_011511929.3 link	c.938T>C	p.Phe313Ser	missense_variant	Exon 5 of 5		XP_011510231.1
WNT10A	XM_011511930.2 link	c.654T>C	p.Leu218Leu	synonymous_variant	Exon 3 of 3		XP_011510232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
WNT10A	ENST00000258411.8 link	c.1034T>C	p.Phe345Ser	missense_variant	Exon 4 of 4	1	NM_025216.3	ENSP00000258411.3
WNT10A	ENST00000458582.1 link	c.540T>C	p.Leu180Leu	synonymous_variant	Exon 2 of 2	3		ENSP00000388812.1
WNT10A	ENST00000489887.1 link	n.-170T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718698

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111060

Other (OTH)

AF:

0.00

AC:

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jun 13, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In 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: 36294409) -

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

Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 345 of the WNT10A protein (p.Phe345Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of odontoonychodermal dysplasia (internal data). ClinVar contains an entry for this variant (Variation ID: 464178). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt WNT10A protein function with a positive predictive value of 80%. This variant disrupts the p.Phe345 amino acid residue in WNT10A. Other variant(s) that disrupt this residue have been observed in individuals with WNT10A-related conditions (PMID: 28976000), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.9

PhyloP100

4.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.92

MutPred

0.72

Gain of phosphorylation at F345 (P = 0.0065);

MVP

0.94

MPC

2.7

ClinPred

1.0

GERP RS

4.9

Varity_R

0.97

gMVP

0.89

Mutation Taster

=8/92

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over