2-218890118-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_025216.3(WNT10A):c.511C>T(p.Arg171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,136 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign 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. R171H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (12 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 B:4
• Conservation: PhyloP100: 1.72

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_025216.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.020337284).
• BS2: High Homozygotes in GnomAdExome at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT10A	NM_025216.3	c.511C>T	p.Arg171Cys	missense_variant	3/4	ENST00000258411.8
WNT10A	XM_011511929.3	c.415C>T	p.Arg139Cys	missense_variant	4/5
WNT10A	XM_011511930.2	c.377-2656C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10A	ENST00000258411.8	c.511C>T	p.Arg171Cys	missense_variant	3/4	1	NM_025216.3	P1
WNT10A	ENST00000458582.1	c.264-2656C>T		intron_variant		3
WNT10A	ENST00000483911.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00191 AC: 480 AN: 251268 Hom.: 2 AF XY: 0.00189 AC XY: 257 AN XY: 135874

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00192 AC: 2813 AN: 1461826 Hom.: 12 Cov.: 32 AF XY: 0.00194 AC XY: 1409 AN XY: 727222

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0134

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00177

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74482

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0147

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00166 Hom.: 2

Bravo AF: 0.00151

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2023	Case-control studies suggest this variant is associated with tooth agenesis (Song et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28265457, 24312213, 30417976, 28981473, 29367877, 24700731, 31103801, 23167694, 34426522, 33034246, 34593752, 36071541, 35546689, 24043634, 24311251, 33329022, 36755192, 36553094) -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Odonto-onycho-dermal dysplasia Uncertain:1 Benign:1

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	Mendelics	May 28, 2019	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

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

Uncertain significance, no assertion criteria provided	clinical testing	Department of Second Dental Center, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine	-	- -
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. -

Tooth agenesis, selective, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Stomatology Center, Xiangya Hospital, Central South University

-

We used whole exome sequencing to compare tooth loss gene loci between two brothers with hypophidrotic ectodermal dysplasia (HED), analyze the difference of tooth loss phenotype, and explore its mechanism. wes showed that an EDA mutation was found in both older and younger brothers (c.878T>G), and the compound heterozygous mutation of WNT10A (c.511C>T and c.637G>A) Found only in the elder brothers. Prediction of secondary and tertiary structures of the WNT10A variants (p. R171C, p.G213S) indicated the impaired function of the molecule. The elder brothers have a more severe tooth loss phenotype than younger brothers. It has been reported that eda c.878T>G mutation caused HED (PMID: 30526585). We believe that EDA is the main pathogenic gene in the two patients, and the complex heterozygous WNT10A missense mutation can aggravate the HED phenotype caused by EDA mutation, resulting in a severe edentulous mandible phenotype in the elder brother. -

SchC6pf-Schulz-Passarge syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.92
MPC		0.40
ClinPred		0.074	T
GERP RS		2.4
Varity_R		0.31
gMVP		0.78

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: rs116998555; hg19: chr2-219754840; COSMIC: COSV99297681; COSMIC: COSV99297681;