chr2-218892834-C-T

Variant names:

• chr2-218892834-C-T
• rs111903177
• NM_025216.3:c.817C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_025216.3(WNT10A):​c.817C>T​(p.Leu273Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L273I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• 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 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_025216.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3886509).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT10A	NM_025216.3	MANE Select	c.817C>T	p.Leu273Phe	missense	Exon 4 of 4	NP_079492.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT10A	ENST00000258411.8	TSL:1 MANE Select	c.817C>T	p.Leu273Phe	missense	Exon 4 of 4	ENSP00000258411.3
	WNT10A	ENST00000458582.1	TSL:3	c.323C>T	p.Ala108Val	missense	Exon 2 of 2	ENSP00000388812.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000480 AC: 1 AN: 208218 AF XY: 0.00000872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000139 AC: 2 AN: 1443558 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 716496

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 38826

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4868

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104702

Other (OTH) AF: 0.00 AC: 0 AN: 59590

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.36
Sift	Benign	0.43	T
Sift4G	Benign	0.28	T
Polyphen		0.060	B
Vest4		0.47
MutPred		0.70		Gain of methylation at K274 (P = 0.0426)
MVP		0.79
MPC		1.1
ClinPred		0.42	T
GERP RS		4.5
Varity_R		0.37
gMVP		0.58
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs111903177; hg19: chr2-219757556;