WNT10A p.Arg69Trp

Variant names:

• chr2-218882252-C-T
• rs200487809
• NM_025216.3:c.205C>T
• WNT10A p.Arg69Trp

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_025216.3(WNT10A):c.205C>T (p.Arg69Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000235 (AC=38) in the gnomAD database across 1,614,170 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000263. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R69Q: Uncertain_significance (ClinVar VariationId 3251508, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.779
• Publications: 1 publications found

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, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Natera, 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000263 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00141) — PM2 supporting.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	WNT10A NM_025216.3	MANE Select	c.205C>T p.Arg69Trp	missense	Exon 2 of 4	Prot: NP_079492.2

WNT10A NM_025216.3

MANE Select

HGVSc / HGVSpc.205C>Tp.Arg69Trp

Exon rankExon 2 of 4

missense

Prot: NP_079492.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	WNT10A ENST00000258411.8	TSL:1MANE Select	c.205C>T p.Arg69Trp	missense	Exon 2 of 4	Prot: ENSP00000258411.3 UniProt:
	WNT10A ENST00000964557.1		c.205C>T p.Arg69Trp	missense	Exon 2 of 6	Prot: ENSP00000634616.1 UniProt:
	WNT10A ENST00000865256.1		c.205C>T p.Arg69Trp	missense	Exon 2 of 4	Prot: ENSP00000535315.1 UniProt:

WNT10A ENST00000258411.8

TSL:1MANE Select

HGVSc / HGVSpc.205C>Tp.Arg69Trp

Exon rankExon 2 of 4

missense

Prot: ENSP00000258411.3UniProt: Q9GZT5

WNT10A ENST00000964557.1

HGVSc / HGVSpc.205C>Tp.Arg69Trp

Exon rankExon 2 of 6

missense

Prot: ENSP00000634616.1UniProt: A0ACI8VE80

WNT10A ENST00000865256.1

HGVSc / HGVSpc.205C>Tp.Arg69Trp

Exon rankExon 2 of 4

missense

Prot: ENSP00000535315.1UniProt: A0ACI8QEH2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000591	AC:9	Hom:0	AN:152172	Cov:32
GnomAD2 exomes	AF: 0.0000438	AC:11	Hom:	AN:251396	Cov:
GnomAD4 exome	AF: 0.0000198	AC:29	Hom:0	AN:1461880	Cov:32
GnomAD4 genome	AF: 0.0000591	AC:9	Hom:0	AN:152290	Cov:32
TOPMed (Bravo)	AF: 0.0000416	AC:11	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000165	AC:5	Hom:0	AN:30298	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000148	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000490	AC:6	Hom:0	AN:122280	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000884	10	113068	0.0000735	14	190422

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 (1)
-	1	-	Schöpf-Schulz-Passarge syndrome (1)
-	1	-	WNT10A-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.51	D
FuncVEP CTI	Pathogenic	0.74
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.35	D
Mutation Taster	N/A	86/14	polymorphism
MutationAssessor	Uncertain	2.8	M
PhyloP100	Benign	0.78
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.58	T
PromoterAI	N/A	0.053	Neutral
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Varity_R	N/A	0.61
VESM-3B	Benign	-10

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200487809;

hg19: chr2-219746974;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar