dbSNP rs1234227647: WNT10A:p.Trp277* (chr2-218892848-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_025216.3(WNT10A):c.831G>A(p.Trp277*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

WNT10A
NM_025216.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.95

Publications

0 publications found

Variant links:

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

WNT10A links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT10A	NM_025216.3 link	c.831G>A	p.Trp277*	stop_gained	Exon 4 of 4	ENST00000258411.8	NP_079492.2	Q9GZT5A0A2K8FR47
WNT10A	XM_011511929.3 link	c.735G>A	p.Trp245*	stop_gained	Exon 5 of 5		XP_011510231.1
WNT10A	XM_011511930.2 link	c.451G>A	p.Ala151Thr	missense_variant	Exon 3 of 3		XP_011510232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT10A	ENST00000258411.8 link	c.831G>A	p.Trp277*	stop_gained	Exon 4 of 4	1	NM_025216.3	ENSP00000258411.3		Q9GZT5
WNT10A	ENST00000458582.1 link	c.337G>A	p.Ala113Thr	missense_variant	Exon 2 of 2	3		ENSP00000388812.1		H7BZB8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712948

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33080

American (AMR)

AF:

0.00

AC:

AN:

42148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25672

East Asian (EAS)

AF:

0.00

AC:

AN:

38466

South Asian (SAS)

AF:

0.00

AC:

AN:

82724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4916

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101918

Other (OTH)

AF:

0.00

AC:

AN:

59362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.9

Vest4

0.83

ClinPred

1.0

GERP RS

4.5

Mutation Taster

=2/198

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over