rs146460077

chr2-218882255-C-T

Variant summary

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

The NM_025216.3(WNT10A):c.208C>T(p.Arg70Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,174 control chromosomes in the GnomAD database, including 8 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. R70R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.497

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=0.037638843).
• BP6: Variant 2-218882255-C-T is Benign according to our data. Variant chr2-218882255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334394.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=1}. Variant chr2-218882255-C-T is described in Lovd as [Likely_benign].
• 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.208C>T	p.Arg70Trp	missense_variant	2/4	ENST00000258411.8
WNT10A	XM_011511929.3	c.112C>T	p.Arg38Trp	missense_variant	3/5
WNT10A	XM_011511930.2	c.208C>T	p.Arg70Trp	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10A	ENST00000258411.8	c.208C>T	p.Arg70Trp	missense_variant	2/4	1	NM_025216.3	P1
WNT10A	ENST00000458582.1	c.97C>T	p.Arg33Trp	missense_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00177 AC: 444 AN: 251386 Hom.: 2 AF XY: 0.00206 AC XY: 280 AN XY: 135880

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00588

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00139 AC: 2028 AN: 1461882 Hom.: 7 Cov.: 32 AF XY: 0.00154 AC XY: 1120 AN XY: 727246

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00604

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74470

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00120 Hom.: 1

Bravo AF: 0.000899

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	Observed in the heterozygous state in two brothers with tooth agenesis; the more severely affected brother was also heterozygous for an EDARADD variant (Arte et al., 2013); Reported along with a second WNT10A variant in a patient with oligodontia in the published literature, but familial segregation information was not included (Arzoo 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: 24449199, 23991204) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	WNT10A: BS2 -

SchC6pf-Schulz-Passarge syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Odonto-onycho-dermal dysplasia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

WNT10A-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The WNT10A c.208C>T variant is predicted to result in the amino acid substitution p.Arg70Trp. This variant has been reported in the heterozygous state in two brothers with missing permanent teeth, and one of the two brothers has more severe phenotype also carried a truncating variant in the EDARADD gene (Arte et al. 2013. PubMed ID: 23991204). This variant is documented in 0.59% of alleles in individuals of South Asian descent in gnomAD. This variant could be benign. At this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Tooth agenesis, selective, 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.0065
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.038	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.90
MPC		0.42
ClinPred		0.067	T
GERP RS		0.68
Varity_R		0.70
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs146460077; hg19: chr2-219746977; COSMIC: COSV51462814; COSMIC: COSV51462814;