chr2-218880974-AGCCCGTCAGGGCCTGCGCGCCATGGGCAGC-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePP5_Moderate

The NM_025216.3(WNT10A):c.-17_13delGTCAGGGCCTGCGCGCCATGGGCAGCGCCC(p.Met1_His5del) variant causes a start lost, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,403,404 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

WNT10A
NM_025216.3 start_lost, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.33

Publications

0 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: ClinGen, 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

WNT10A links:

ENSG00000300702 (HGNC:):

ENSG00000300702 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_025216.3 (WNT10A) was described as [Likely_pathogenic] in ClinVar as 1466056

PP5

Variant 2-218880974-AGCCCGTCAGGGCCTGCGCGCCATGGGCAGC-A is Pathogenic according to our data. Variant chr2-218880974-AGCCCGTCAGGGCCTGCGCGCCATGGGCAGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067133.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT10A	NM_025216.3 link	c.-17_13delGTCAGGGCCTGCGCGCCATGGGCAGCGCCC	p.Met1_His5del	start_lost, conservative_inframe_deletion	Exon 1 of 4	ENST00000258411.8	NP_079492.2	Q9GZT5A0A2K8FR47
WNT10A	NM_025216.3 link	c.-17_13delGTCAGGGCCTGCGCGCCATGGGCAGCGCCC		5_prime_UTR_variant	Exon 1 of 4	ENST00000258411.8	NP_079492.2	Q9GZT5A0A2K8FR47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WNT10A	ENST00000258411.8 link	c.-17_13delGTCAGGGCCTGCGCGCCATGGGCAGCGCCC	p.Met1_His5del	start_lost, conservative_inframe_deletion	Exon 1 of 4	1	NM_025216.3	ENSP00000258411.3	Q9GZT5
WNT10A	ENST00000258411.8 link	c.-17_13delGTCAGGGCCTGCGCGCCATGGGCAGCGCCC		5_prime_UTR_variant	Exon 1 of 4	1	NM_025216.3	ENSP00000258411.3	Q9GZT5
ENSG00000300702	ENST00000773519.1 link	n.127_156delGCCCGTCAGGGCCTGCGCGCCATGGGCAGC		downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000263

AC:

AN:

152178

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000155

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1403404

Hom.:

AF XY:

0.00000289

AC XY:

AN XY:

692978

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31936

American (AMR)

AF:

0.0000813

AC:

AN:

36912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25050

East Asian (EAS)

AF:

0.00

AC:

AN:

36392

South Asian (SAS)

AF:

0.00

AC:

AN:

80072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4944

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081884

Other (OTH)

AF:

0.00

AC:

AN:

58016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.013624), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the WNT10A mRNA. The next in-frame methionine is located at codon 36. This variant is present in population databases (rs746813123, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive ectodermal dysplasia (PMID: 23401279). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1067133). This variant disrupts a region of the WNT10A protein in which other variant(s) (p.Leu29Arg) have been observed in individuals with WNT10A-related conditions (PMID: 23401279). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.3

Splicing

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

Publications

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chr2-218880974-AGCCCGTCAGGGCCTGCGCGCCATGGGCAGC-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over