rs116998555

Variant names:

• chr2-218890118-C-T
• rs116998555
• NM_025216.3:c.511C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-218890118-C-T
• chr2-218890118-C-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BS1 BS2

The NM_025216.3(WNT10A):​c.511C>T​(p.Arg171Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,136 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (12 hom.)
• Consequence: WNT10A NM_025216.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9 B:4
• Conservation: PhyloP100: 1.72
• Publications: 28 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: Illumina, ClinGen
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_025216.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.020337284).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00129 (196/152310) while in subpopulation EAS AF = 0.0147 (76/5180). AF 95% confidence interval is 0.012. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.511C>T	p.Arg171Cys	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.511C>T	p.Arg171Cys	missense	Exon 3 of 4	ENSP00000258411.3	Q9GZT5
	WNT10A	ENST00000964557.1		c.826C>T	p.Arg276Cys	missense	Exon 5 of 6	ENSP00000634616.1
	WNT10A	ENST00000865256.1		c.541C>T	p.Arg181Cys	missense	Exon 3 of 4	ENSP00000535315.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00191 AC: 480 AN: 251268 AF XY: 0.00189

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0158

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00192 AC: 2813 AN: 1461826 Hom.: 12 Cov.: 32 AF XY: 0.00194 AC XY: 1409 AN XY: 727222

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0134 AC: 531 AN: 39700

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86256

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53388

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00177 AC: 1973 AN: 1112006

Other (OTH) AF: 0.00224 AC: 135 AN: 60392

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74482

African (AFR) AF: 0.000409 AC: 17 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0147 AC: 76 AN: 5180

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68018

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00157 Hom.: 3

Bravo AF: 0.00151

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	4	-	not provided (5)
-	1	1	Odonto-onycho-dermal dysplasia (2)
-	1	1	Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4 (2)
-	1	1	Tooth agenesis, selective, 4 (2)
-	1	-	Odonto-onycho-dermal dysplasia;C1835492:Tooth agenesis, selective, 4;C1857069:Schöpf-Schulz-Passarge syndrome (1)
-	-	1	Schöpf-Schulz-Passarge syndrome (1)
1	-	-	Tooth agenesis, selective, 2 (1)
-	1	-	WNT10A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.92
MPC		0.40
ClinPred		0.074	T
GERP RS		2.4
Varity_R		0.31
gMVP		0.78
Mutation Taster		=49/51	disease causing (ClinVar)

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: rs116998555; hg19: chr2-219754840; COSMIC: COSV99297681; COSMIC: COSV99297681;