11-32392019-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate
The NM_024426.6(WT1):c.1400G>C(p.Arg467Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467L) has been classified as Pathogenic.
Frequency
Consequence
NM_024426.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WT1 | NM_024426.6 | c.1400G>C | p.Arg467Pro | missense_variant | 9/10 | ENST00000452863.10 | NP_077744.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WT1 | ENST00000452863.10 | c.1400G>C | p.Arg467Pro | missense_variant | 9/10 | 1 | NM_024426.6 | ENSP00000415516.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Drash syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1992 | - - |
WT1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 06, 2022 | The WT1 c.1385G>C variant is predicted to result in the amino acid substitution p.Arg462Pro. This variant is alternatively referred to as p.Arg394Pro using Legacy nomenclature. It is also referred to as NM_024426.6:c.1400G>C (p.Arg467Pro) using an updated version of this transcript. This variant has been reported in individuals with Denys-Drash syndrome (Fig. 3, Bruening et al. 1992. PubMed ID: 1302008; Table S1, Lehnhardt. 2015. PubMed ID: 25818337). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Alternate nucleotide changes affecting the same amino acid (p.Arg462Gln, p.Arg462Gly, p.Arg462Leu, and p.Arg462Trp) have been reported in individuals with WT1-related disease (Table 1, Pelletier et al. 1991. PubMed ID: 1655284; Jeanpierre et al. 1998. PubMed ID: 9529364; Royer-Pokora et al. 2004. PubMed ID: 15150775; Table 1, Chernin et al. 2010. PubMed ID: 20595692; Table S1, Lehnhardt. 2015. PubMed ID: 25818337). Of note, the alternate p.Arg462Trp (aka p.Arg467Trp) change is reported to be a hotspot variant for Denys-Drash syndrome (Table 6, Lipska-Zietkiewicz et al. 2020. PubMed ID: 32352694). The c.1385G>C (p.Arg462Pro) variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at