11-32428521-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBP6BS2
The NM_024426.6(WT1):c.760C>A(p.Pro254Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000052 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P254S) has been classified as Pathogenic.
Frequency
Consequence
NM_024426.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WT1 | ENST00000452863.10 | c.760C>A | p.Pro254Thr | missense_variant | Exon 2 of 10 | 1 | NM_024426.6 | ENSP00000415516.5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251132Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135842
GnomAD4 exome AF: 0.0000547 AC: 80AN: 1461804Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38AN XY: 727212
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74482
ClinVar
Submissions by phenotype
11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2025 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 249 of the WT1 protein (p.Pro249Thr). This variant is present in population databases (rs2234584, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of WT1-related conditions (PMID: 32604935). This variant is also known as c.760C>A. ClinVar contains an entry for this variant (Variation ID: 864601). 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
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 11, 2024 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at