rs77583146

Variant names:

• chr2-218890100-G-A
• rs77583146
• NM_025216.3:c.493G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025216.3(WNT10A):​c.493G>A​(p.Gly165Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,184 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G165G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (4 hom., cov: 33)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 7.87
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012216538).
• BP6: Variant 2-218890100-G-A is Benign according to our data. Variant chr2-218890100-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334399.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00717 (1093/152358) while in subpopulation NFE AF = 0.0122 (830/68036). AF 95% confidence interval is 0.0115. There are 4 homozygotes in GnomAd4. There are 491 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT10A	NM_025216.3	MANE Select	c.493G>A	p.Gly165Arg	missense	Exon 3 of 4	NP_079492.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT10A	ENST00000258411.8	TSL:1 MANE Select	c.493G>A	p.Gly165Arg	missense	Exon 3 of 4	ENSP00000258411.3
	WNT10A	ENST00000964557.1		c.808G>A	p.Gly270Arg	missense	Exon 5 of 6	ENSP00000634616.1
	WNT10A	ENST00000865256.1		c.523G>A	p.Gly175Arg	missense	Exon 3 of 4	ENSP00000535315.1

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1093 AN: 152240 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00685 AC: 1722 AN: 251334 AF XY: 0.00669

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00949

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.0106 AC: 15516 AN: 1461826 Hom.: 104 Cov.: 32 AF XY: 0.0104 AC XY: 7541 AN XY: 727220

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00242 AC: 108 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86252

European-Finnish (FIN) AF: 0.0105 AC: 558 AN: 53374

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5760

European-Non Finnish (NFE) AF: 0.0127 AC: 14141 AN: 1112010

Other (OTH) AF: 0.00945 AC: 571 AN: 60396

GnomAD4 genome AF: 0.00717 AC: 1093 AN: 152358 Hom.: 4 Cov.: 33 AF XY: 0.00659 AC XY: 491 AN XY: 74504

African (AFR) AF: 0.00190 AC: 79 AN: 41582

American (AMR) AF: 0.00281 AC: 43 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0122 AC: 830 AN: 68036

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00947 Hom.: 22

Bravo AF: 0.00669

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00731 AC: 888

EpiCase AF: 0.00943

EpiControl AF: 0.00978

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Schöpf-Schulz-Passarge syndrome (3)
-	1	1	not provided (2)
-	-	2	Odonto-onycho-dermal dysplasia (2)
-	1	1	Tooth agenesis, selective, 4 (2)
-	-	1	Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 (1)
-	1	-	Tooth agenesis (1)
-	-	1	WNT10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.35
Sift	Benign	0.032	D
Sift4G	Benign	0.24	T
Polyphen		0.11	B
Vest4		0.83
MutPred		0.49		Loss of helix (P = 0.028)
MVP		0.86
MPC		0.46
ClinPred		0.030	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.80
Mutation Taster		=68/32	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: rs77583146; hg19: chr2-219754822;