2-218892848-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_025216.3(WNT10A):c.831G>T(p.Trp277Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,589,770 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_025216.3 (WNT10A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1175006
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT10A	NM_025216.3	c.831G>T	p.Trp277Cys	missense_variant	4/4	ENST00000258411.8
WNT10A	XM_011511929.3	c.735G>T	p.Trp245Cys	missense_variant	5/5
WNT10A	XM_011511930.2	c.451G>T	p.Ala151Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10A	ENST00000258411.8	c.831G>T	p.Trp277Cys	missense_variant	4/4	1	NM_025216.3	P1
WNT10A	ENST00000458582.1	c.340G>T	p.Ala114Ser	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437542 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 2 AN XY: 712948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000237

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

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

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

SchC6pf-Schulz-Passarge syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 13, 2020

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2023

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with both dominant and recessive WNT10A-related disease (PMID: 22581971, 24700731, 26087098, 28976000; Invitae). ClinVar contains an entry for this variant (Variation ID: 532830). 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. 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 277 of the WNT10A protein (p.Trp277Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.89		Gain of disorder (P = 0.0063);
MVP		0.97
MPC		2.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.91

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

Other links and lift over

dbSNP: rs1234227647; hg19: chr2-219757570;