NM_024426.6:c.1463G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4BP6BS2_Supporting

The NM_024426.6(WT1):c.1463G>A(p.Ser488Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. S488S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

WT1
NM_024426.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.28

Publications

2 publications found

Variant links:

Genes affected

WT1 (HGNC:12796): (WT1 transcription factor) This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilms tumor. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation codon upstream of, and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Mar 2015]

WT1 Gene-Disease associations (from GenCC):

Denys-Drash syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
Wilms tumor 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Frasier syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35612145).

BP6

Variant 11-32389164-C-T is Benign according to our data. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335. Variant chr11-32389164-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 78335.

BS2

High AC in GnomAdExome4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6 link	c.1463G>A	p.Ser488Asn	missense_variant	Exon 10 of 10	ENST00000452863.10	NP_077744.4	P19544-7Q6PI38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 link	c.1463G>A	p.Ser488Asn	missense_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1

Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 483 of the WT1 protein (p.Ser483Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 78335). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt WT1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Mar 11, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.16

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.88

D;.;D;.;.;.;.;.

M_CAP

Benign

0.0066

MetaRNN

Benign

0.36

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.3

N;N;N;N;N;.;.;.

REVEL

Benign

0.050

Sift

Benign

0.22

T;T;T;T;T;.;.;.

Sift4G

Benign

0.29

T;T;T;T;T;.;.;.

Polyphen

0.0

B;.;.;.;.;.;.;.

Vest4

0.11

MVP

0.32

ClinPred

0.76

GERP RS

4.7

gMVP

0.54

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over