chr2-218890289-T-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3PM1PP3PP5BP4

The NM_025216.3(WNT10A):c.682T>A(p.Phe228Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,608,024 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005422991: "The variant disrupts WNT signaling (Zeng_2020)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F228L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 22 hom., cov: 32)

Exomes 𝑓: 0.021 ( 427 hom. )

Consequence

WNT10A
NM_025216.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:33U:2O:3

Conservation

PhyloP100: 7.94

Publications

97 publications found

Variant links:

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 Classification: DEFINITIVE Submitted by: Illumina, ClinGen
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: Orphanet, Labcorp Genetics (formerly Invitae)
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

WNT10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV005422991: "The variant disrupts WNT signaling (Zeng_2020)."; SCV004175284: Large meta analysis shows 2.25 - 3.42 fold increased risk for isolated tooth agenesis (PMID:29364747) (PS3).

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_025216.3

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 2-218890289-T-A is Pathogenic according to our data. Variant chr2-218890289-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4462.

BP4

Computational evidence support a benign effect (MetaRNN=0.013546854). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT10A	NM_025216.3	MANE Select	c.682T>A	p.Phe228Ile	missense	Exon 3 of 4	NP_079492.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WNT10A	ENST00000258411.8	TSL:1 MANE Select	c.682T>A	p.Phe228Ile	missense	Exon 3 of 4	ENSP00000258411.3	Q9GZT5
WNT10A	ENST00000964557.1		c.997T>A	p.Phe333Ile	missense	Exon 5 of 6	ENSP00000634616.1
WNT10A	ENST00000865256.1		c.712T>A	p.Phe238Ile	missense	Exon 3 of 4	ENSP00000535315.1

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2138

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0139

AC:

3389

AN:

243534

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.00372

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0349

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00470

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0215

AC:

31289

AN:

1455814

Hom.:

427

Cov.:

AF XY:

0.0212

AC XY:

15348

AN XY:

724498

show subpopulations

African (AFR)

AF:

0.00358

AC:

120

AN:

33480

American (AMR)

AF:

0.0113

AC:

504

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0353

AC:

923

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00186

AC:

160

AN:

86252

European-Finnish (FIN)

AF:

0.00531

AC:

252

AN:

47450

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0254

AC:

28218

AN:

1111952

Other (OTH)

AF:

0.0172

AC:

1040

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1967

3933

5900

7866

9833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1106

2212

3318

4424

5530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0140

AC:

2138

AN:

152210

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

934

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00407

AC:

169

AN:

41522

American (AMR)

AF:

0.0156

AC:

239

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

120

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1515

AN:

67990

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0225

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00727

AC:

ESP6500EA

AF:

0.0243

AC:

209

ExAC

AF:

0.0125

AC:

1517

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tooth agenesis, selective, 4 (8)

not provided (7)

Odonto-onycho-dermal dysplasia (6)

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4;C1857069:Schöpf-Schulz-Passarge syndrome (5)

Ectodermal dysplasia (3)

Hypohidrotic ectodermal dysplasia (2)

Ectodermal dysplasia WNT10A related (1)

Inborn genetic diseases (1)

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

See cases (1)

Tooth agenesis (1)

Tooth agenesis, selective, 4;C1857069:Schöpf-Schulz-Passarge syndrome (1)

WNT10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.4

PhyloP100

7.9

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.35

MPC

0.50

ClinPred

0.060

GERP RS

4.5

Varity_R

0.87

gMVP

0.84

Mutation Taster

=23/77

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over