rs776155094
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_024426.6(WT1):c.151delG(p.Ala51ProfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000391 in 1,533,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024426.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WT1 | ENST00000452863.10 | c.151delG | p.Ala51ProfsTer31 | frameshift_variant | Exon 1 of 10 | 1 | NM_024426.6 | ENSP00000415516.5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152108Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000762 AC: 1AN: 131284Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 71976
GnomAD4 exome AF: 0.00000217 AC: 3AN: 1380958Hom.: 0 Cov.: 44 AF XY: 0.00000294 AC XY: 2AN XY: 681070
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152108Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Precursor B-cell acute lymphoblastic leukemia Pathogenic:1
This is a frameshift variant, in which a G is deleted at coding position 136 and is predicted to change an Alanine to a Proline and shift the reading frame. -
11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Uncertain:1
This sequence change creates a premature translational stop signal (p.Ala46Profs*31) in the WT1 gene. It is unclear whether it will result in an absent or disrupted protein product because a major initiation site located at codon 69 has the potential to rescue this variant. This variant is present in population databases (rs776155094, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with anaplastic astrocytoma (PMID: 31970404). ClinVar contains an entry for this variant (Variation ID: 265295). Downstream of the non-canonical translation start site (CTG) at codon 1, the nearest methionine codon that can be used to initiate translation of the WT1 protein lies at codon 69. This downstream in-frame ATG is known as a major initiation site (PMID: 28811308, 16987884, 8621495). The functional significance of the different WT1 protein isoforms is unknown (PMID: 8621495), however mice lacking the N-terminal 68 amino acids develop normally and are fertile (PMID: 12640141). Based on these results, the impact of this variant on WT1 protein function is uncertain. 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. -
Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Uncertain:1
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Drash syndrome Uncertain:1
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not provided Uncertain:1
Nonsense variant predicted to result in protein truncation; however a downstream in-frame ATG could serve as an alternate initiator codon which may result in a smaller, yet still functional, protein (Bruenig et al., 1996; Scharnhorst et al., 1999; Yang et al., 2007).; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with pancreatic cancer and pediatric glioma (Skaro et al., 2019; Muskens et al., 2020); Also known as c.151del/p.(A51Pfs*31); This variant is associated with the following publications: (PMID: 26633542, 30665703, 31970404, 30716324, 8621495, 10438524, 17361230) -
WT1-related disorder Uncertain:1
The WT1 c.136delG variant is predicted to result in a frameshift and premature protein termination (p.Ala46Profs*31). This variant has been reported in an individual with anaplastic astrocytoma (Muskens et al. 2020. PubMed ID: 31970404) and another individual with intraductal papillary mucinous neoplasms (IPMNs) at risk for developing pancreatic cancer (Skaro et al. 2019. PubMed ID: 30716324), but it has not been reported in patients with established WT-related disorders. This variant would typically be expected to cause a frameshift leading to premature termination; however there is a downstream, in-frame methionine residue (p.Met69) that has been shown to act as an alternate initiation site and potentially rescue WT1 translation (Bruening and Pelletier. 1996. PubMed ID: 8621495; Scharnhorst et al. 1999. PubMed ID: 10438524). Furthermore, significant N-terminal variation has been observed in functional WT1 isoforms (same studies), and a mouse model lacking the 68 N-terminal amino acids developed normally and remained capable of reproduction (Miles et al. 2003. PubMed ID: 12640141). This variant is reported in 0.0020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/265295/). Taken together, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at