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
Consequence
NM_024426.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WT1 | ENST00000452863.10 | c.760C>T | p.Pro254Ser | missense_variant | Exon 2 of 10 | 1 | NM_024426.6 | ENSP00000415516.5 |
Frequencies
GnomAD3 genomes AF: 0.000401 AC: 61AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000390 AC: 98AN: 251132Hom.: 0 AF XY: 0.000412 AC XY: 56AN XY: 135842
GnomAD4 exome AF: 0.000525 AC: 767AN: 1461804Hom.: 1 Cov.: 33 AF XY: 0.000509 AC XY: 370AN XY: 727212
GnomAD4 genome AF: 0.000400 AC: 61AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
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WT1: PM5:Supporting, PS4:Supporting, BP4, BS1 -
See Variant Classification Assertion Criteria. -
not specified Uncertain:2Benign:1Other:1
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. -
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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. -
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
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11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Benign:1
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Inborn genetic diseases Benign:1
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
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Meacham syndrome Benign:1
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
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
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
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Wilms tumor 1 Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at