Genetic Variant WNT10A:p.Cys404Trp (chr2-218893229-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_025216.3(WNT10A):c.1212C>G(p.Cys404Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C404F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WNT10A
NM_025216.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.869

Publications

0 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 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT10A	NM_025216.3	MANE Select	c.1212C>G	p.Cys404Trp	missense	Exon 4 of 4	NP_079492.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WNT10A	ENST00000258411.8	TSL:1 MANE Select	c.1212C>G	p.Cys404Trp	missense	Exon 4 of 4	ENSP00000258411.3
WNT10A	ENST00000964557.1		c.1527C>G	p.Cys509Trp	missense	Exon 6 of 6	ENSP00000634616.1
WNT10A	ENST00000865256.1		c.1242C>G	p.Cys414Trp	missense	Exon 4 of 4	ENSP00000535315.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412654

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699024

African (AFR)

AF:

0.00

AC:

AN:

32800

American (AMR)

AF:

0.00

AC:

AN:

39888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25556

East Asian (EAS)

AF:

0.00

AC:

AN:

38210

South Asian (SAS)

AF:

0.00

AC:

AN:

82500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093560

Other (OTH)

AF:

0.00

AC:

AN:

58952

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.3

PhyloP100

0.87

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-9.8

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.83

Loss of sheet (P = 0.0817)

MVP

0.96

MPC

2.4

ClinPred

1.0

GERP RS

2.1

Varity_R

0.98

gMVP

0.97

Mutation Taster

=1/99

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over