2-218880996-A-T

Variant names:

• chr2-218880996-A-T
• rs1221516695
• NM_025216.3:c.1A>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_025216.3(WNT10A):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: WNT10A NM_025216.3 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.434

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 36 codons. Genomic position: 218881101. Lost 0.085 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-218880996-A-T is Pathogenic according to our data. Variant chr2-218880996-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1466056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218880996-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT10A	NM_025216.3	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 4	ENST00000258411.8	NP_079492.2
WNT10A	XM_011511930.2	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 3		XP_011510232.1
WNT10A	XM_011511929.3	c.18-1165A>T		intron_variant	Intron 2 of 4		XP_011510231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT10A	ENST00000258411.8	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 4	1	NM_025216.3	ENSP00000258411.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000575 AC: 1 AN: 174052 Hom.: 0 AF XY: 0.0000105 AC XY: 1 AN XY: 95410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 7.04e-7 AC: 1 AN: 1420112 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000253

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4;C1857069:SchC6pf-Schulz-Passarge syndrome Pathogenic:1

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 30974434). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1466056). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive WNT10A-related conditions (PMID: 23401279). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the WNT10A mRNA. The next in-frame methionine is located at codon 36. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.73	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.90
MutPred		0.95		Loss of MoRF binding (P = 0.0777);
MVP		0.78
ClinPred		0.83	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.38

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: rs1221516695; hg19: chr2-219745718;