rs77583146

Positions:

• chr2-218890100-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_025216.3(WNT10A):​c.493G>A​(p.Gly165Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,184 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G165G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (4 hom., cov: 33)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 7.87

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012216538).
• BP6: Variant 2-218890100-G-A is Benign according to our data. Variant chr2-218890100-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334399.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=5}. Variant chr2-218890100-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT10A	NM_025216.3	c.493G>A	p.Gly165Arg	missense_variant	3/4	ENST00000258411.8
WNT10A	XM_011511929.3	c.397G>A	p.Gly133Arg	missense_variant	4/5
WNT10A	XM_011511930.2	c.377-2674G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10A	ENST00000258411.8	c.493G>A	p.Gly165Arg	missense_variant	3/4	1	NM_025216.3	P1
WNT10A	ENST00000458582.1	c.264-2674G>A		intron_variant		3
WNT10A	ENST00000483911.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1093 AN: 152240 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00685 AC: 1722 AN: 251334 Hom.: 11 AF XY: 0.00669 AC XY: 909 AN XY: 135888

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00949

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.0106 AC: 15516 AN: 1461826 Hom.: 104 Cov.: 32 AF XY: 0.0104 AC XY: 7541 AN XY: 727220

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.00945

GnomAD4 genome AF: 0.00717 AC: 1093 AN: 152358 Hom.: 4 Cov.: 33 AF XY: 0.00659 AC XY: 491 AN XY: 74504

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00838

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00980 Hom.: 16

Bravo AF: 0.00669

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00731 AC: 888

EpiCase AF: 0.00943

EpiControl AF: 0.00978

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

SchC6pf-Schulz-Passarge syndrome Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 30, 2019	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	Observed in the heterozygous state or as compound heterozygous with another variant in the WNT10A gene in both individuals with oligodontia as well as in unaffected individuals, and was reported as a polymorphism (Bohring et al., 2009; Yang et al., 2015; Mostowska et al., 2015); Observed in individuals with tooth agenesis in published literature who had variants in other genes associated with ectodermal anomalies (Arte et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33311554, 19559398, 25545742, 30426266, 23991204, 25629078, 30555066, 31798653, 36250548) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	WNT10A: BS1, BS2 -

Tooth agenesis, selective, 4 Uncertain:1 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Odonto-onycho-dermal dysplasia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 15, 2014

- -

WNT10A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.35
Sift	Benign	0.032	D
Sift4G	Benign	0.24	T
Polyphen		0.11	B
Vest4		0.83
MutPred		0.49		Loss of helix (P = 0.028);
MVP		0.86
MPC		0.46
ClinPred		0.030	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.80

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: rs77583146; hg19: chr2-219754822;