rs2234584

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024426.6(WT1):​c.760C>T​(p.Pro254Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000513 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00052 ( 1 hom. )

Consequence

WT1
NM_024426.6 missense

Scores

1
5
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13O:1

Conservation

PhyloP100: 6.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.056760073).
BS2
High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WT1NM_024426.6 linkc.760C>T p.Pro254Ser missense_variant Exon 2 of 10 ENST00000452863.10 NP_077744.4 P19544-7Q6PI38

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WT1ENST00000452863.10 linkc.760C>T p.Pro254Ser missense_variant Exon 2 of 10 1 NM_024426.6 ENSP00000415516.5 P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes
AF:
0.000401
AC:
61
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000981
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000573
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000390
AC:
98
AN:
251132
Hom.:
0
AF XY:
0.000412
AC XY:
56
AN XY:
135842
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000418
Gnomad NFE exome
AF:
0.000678
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000525
AC:
767
AN:
1461804
Hom.:
1
Cov.:
33
AF XY:
0.000509
AC XY:
370
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000431
Gnomad4 NFE exome
AF:
0.000627
Gnomad4 OTH exome
AF:
0.000530
GnomAD4 genome
AF:
0.000400
AC:
61
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.000456
AC XY:
34
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.000573
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000473
Hom.:
0
Bravo
AF:
0.000325
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000582
AC:
5
ExAC
AF:
0.000379
AC:
46
EpiCase
AF:
0.000818
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:13Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

WT1: PM5:Supporting, PS4:Supporting, BP4, BS1 -

Mar 08, 2024
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

not specified Uncertain:2Benign:1Other:1
Oct 01, 2020
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DNA sequence analysis of the WT1 gene demonstrated a sequence change, c.760C>T, in exon 2 that results in an amino acid change, p.Pro254Ser. This sequence change has been described in the gnomAD database with a frequency of 0.063% in the European sub-population (dbSNP rs2234584). The p.Pro254Ser change has been identified in one individual with Wilm's tumor and another individual with 46,XY disorder of sexual development (PMIDs: 9108089, 21508141). The p.Pro254Ser change affects a moderately conserved amino acid residue located in a domain of the WT1 protein that is known to be functional. The p.Pro254Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro254Ser change remains unknown at this time. -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Jan 10, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: WT1 c.760C>T (p.Pro254Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 1461804 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 55.97 fold of the estimated maximal expected allele frequency for a pathogenic variant in WT1 causing Wilms Tumor, Type 1 phenotype (9.4e-06). c.760C>T has been reported in the literature in individuals affected with Wilms Tumor, amongts other phenotypes (ie: Schumacher_1997, etc). These report(s) do not provide unequivocal conclusions about association of the variant with Wilms Tumor, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9108089). ClinVar contains an entry for this variant (Variation ID: 135453). Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 25, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified this year. The variant has been reported in 4 papers: 1 patient with wilms tumor but no second somatic mutation, 1 healthy indvidual, 1 with abnormal sex development, and one with ureteropelvic junction obstruction in which it was predicted to be VUS. It has been seen in 40/66282 alleles in ExAC (0.06%) (too high for disease/gene contribution?). -

Microscopic hematuria Uncertain:1
Feb 15, 2022
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Sep 11, 2024
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Nephroblastoma Benign:1
Sep 16, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Meacham syndrome Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nephrotic syndrome, type 4 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

WT1-related disorder Benign:1
Oct 15, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1
Nov 05, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Wilms tumor 1 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.057
T
BayesDel_noAF
Uncertain
0.050
CADD
Benign
23
DANN
Pathogenic
1.0
Eigen
Benign
-0.056
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;.;D;.;.;.;.;.
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.057
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.51
T
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-1.6
N;N;N;N;N;.;.;.
REVEL
Uncertain
0.42
Sift
Benign
0.14
T;T;T;T;T;.;.;.
Sift4G
Benign
0.80
T;T;T;T;T;.;.;.
Polyphen
0.0040
B;.;.;.;.;.;.;.
Vest4
0.82
MVP
0.71
ClinPred
0.056
T
GERP RS
5.6
gMVP
0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2234584; hg19: chr11-32450067; COSMIC: COSV60071168; API