NM_025216.3:c.817C>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025216.3(WNT10A):​c.817C>A​(p.Leu273Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,595,902 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L273L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0089 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (11 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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: Benign. The variant received -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.011193067).
• BP6: Variant 2-218892834-C-A is Benign according to our data. Variant chr2-218892834-C-A is described in ClinVar as Benign. ClinVar VariationId is 334405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00888 (1353/152344) while in subpopulation AFR AF = 0.0307 (1276/41580). AF 95% confidence interval is 0.0293. There are 20 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR,SD,AD gene

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>A	p.Leu273Ile	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>A	p.Leu273Ile	missense	Exon 4 of 4	ENSP00000258411.3
	WNT10A	ENST00000458582.1	TSL:3	c.323C>A	p.Ala108Asp	missense	Exon 2 of 2	ENSP00000388812.1

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1341 AN: 152226 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00208 AC: 433 AN: 208218 AF XY: 0.00159

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000674

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.000798 AC: 1152 AN: 1443558 Hom.: 11 Cov.: 31 AF XY: 0.000694 AC XY: 497 AN XY: 716496

African (AFR) AF: 0.0291 AC: 966 AN: 33162

American (AMR) AF: 0.00132 AC: 57 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: 0.0000599 AC: 5 AN: 83452

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

Middle Eastern (MID) AF: 0.00103 AC: 5 AN: 4868

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1104702

Other (OTH) AF: 0.00161 AC: 96 AN: 59590

GnomAD4 genome AF: 0.00888 AC: 1353 AN: 152344 Hom.: 20 Cov.: 32 AF XY: 0.00844 AC XY: 629 AN XY: 74492

African (AFR) AF: 0.0307 AC: 1276 AN: 41580

American (AMR) AF: 0.00405 AC: 62 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00206 Hom.: 3

Bravo AF: 0.00992

ESP6500AA AF: 0.0280 AC: 119

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00245 AC: 291

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.096	T
Polyphen		0.44	B
Vest4		0.49
MVP		0.84
MPC		1.7
ClinPred		0.011	T
GERP RS		4.5
Varity_R		0.42
gMVP		0.35
Mutation Taster		=57/43	polymorphism

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;