11-32391967-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_024426.6(WT1):c.1447+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
WT1
NM_024426.6 splice_region, intron
NM_024426.6 splice_region, intron
Scores
1
1
Clinical Significance
Conservation
PhyloP100: 7.87
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-32391967-C-T is Pathogenic according to our data. Variant chr11-32391967-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32391967-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WT1 | NM_024426.6 | c.1447+5G>A | splice_region_variant, intron_variant | ENST00000452863.10 | NP_077744.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| WT1 | ENST00000452863.10 | c.1447+5G>A | splice_region_variant, intron_variant | 1 | NM_024426.6 | ENSP00000415516.5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460698Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726750
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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31
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Nov 09, 2020 | PS3, PS4, PP3, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2019 | Published functional studies demonstrate a damaging effect: aberrant splicing resulting in disruption of the ratio of WT1 isoforms (Bruening 1992, Klamt 1998); Not observed in large population cohorts (Lek 2016); Also known as c.1228+5G>A; This variant is associated with the following publications: (PMID: 32203225, 31447099, 7959750, 8281163, 1302008, 9499425, 30406062, 28780565, 28204945, 25818337, 20442690, 23515051, 10505700, 11354777) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 14, 2019 | Not found in the total gnomAD dataset, and the data is high quality. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. 3 de novo cases with parental identity not confirmed. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 21, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 24, 2023 | - - |
Frasier syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 16, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1998 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) (GeneReviews); and Wilms tumor, type 1 (MIM#194070), respectively. (I) 0107 - This gene is associated with autosomal dominant disease. It is noted that Denys-Drash syndrome (MIM#194080), Frasier syndrome (MIM#136680), Meacham syndrome (MIM#608978) and nephrotic syndrome, type 4 (MIM#256370) represent a phenotypic continuum (ClinGen Expert Panel). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Minigene assay and RT-PCR of cDNA obtained from gonadal tissue of an affected individual demonstrated aberrant splicing, leading to a reduction in +KTS isoform (PMIDs: 1302008, 9499425). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals described as having Frasier syndrome and steroid-resistant nephrotic syndrome, type 4 , including de novo events (PMIDs: 16439601, 25623218; DECIPHER). It is also consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Nephrotic syndrome, type 4 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.83). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 23515051). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003493 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous c.1432+5G>A variant in WT1 was identified by our study in one individual with steroid-resistant nephrotic syndrome. Trio exome analysis revealed this variant to be de novo. The c.1432+5G>A variant in WT1 has been reported in 19 unrelated individuals with WT1 disorder (PMID: 23295293, PMID: 27719739, PMID: 21499692, PMID: 22099579, PMID: 24856380, PMID: 10762296, PMID: 20442690, PMID: 9499425, PMID: 1302008). This variant was found to be de novo in 13 individuals with confirmed paternity and maternity (PMID: 28204945, PMID: 28780565, PMID: 23515051, PMID: 21499692, PMID: 17694336, PMID: 10762296, PMID: 9499425, PMID: 1302008). This variant is assumed de novo in 10 individuals, but maternity and paternity have not been confirmed (PMID: 23295293, PMID: 27719739, PMID: 28204945, PMID: 22099579, PMID: 24856380, PMID: 9499425). This variant has also been reported in ClinVar (Variation ID: 3493) and has been interpreted as pathogenic by multiple submitters. Multiple variants in the same region as the c.1432+5G>A variant have been reported in association with disease, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 9499425). This variant was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. RT-PCR analysis performed on affected tissue shows this variant results in altered splicing of WT1, leading to an altered ratio of the +/- KTS isoforms (PMID: 17694336, PMID: 9499425, PMID: 1302008). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant WT1 disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3_Moderate, PS4, PM1_Supporting, PM2_Supporting (Richards 2015). - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | May 17, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Mar 14, 2024 | This variant lies in the splice donor site, in intron 9 of the WT1 gene. In silico splice prediction tools (ASSP and NNSPLICE) predicted this variant to interfere with splicing. The variant (also known as 1228+5G>A and IVS9+5G>A) has been reported in the in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome [PMID: 23515051, 1302008, 20442690]. In vitro functional studies indicate that this variant results in defective splicing resulting in disruption of the ratio of WT1 isoforms [PMID: 9499425]. - |
Drash syndrome Pathogenic:3
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1992 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Feb 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Jan 27, 2022 | - - |
Wilms tumor 1 Pathogenic:1Other:1
| not provided, no classification provided | literature only | GeneReviews | - | Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 02, 2023 | - - |
11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 13, 2023 | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 9 (PMID: 1302008, 9499425). ClinVar contains an entry for this variant (Variation ID: 3493). This variant is also known as IVS9+5G>A and c.1228+5G>A. This variant has been observed in individual(s) with Frasier syndrome and/or steroid-resistant nephrotic syndrome (PMID: 9499425, 20442690, 25818337, 27719739). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the WT1 gene. It does not directly change the encoded amino acid sequence of the WT1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. - |
11p partial monosomy syndrome;C0344542:Aniridia 1;C0345967:Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 19, 2022 | - - |
Familial idiopathic steroid-resistant nephrotic syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 02, 2015 | - - |
WT1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2024 | The WT1 c.1432+5G>A variant is predicted to interfere with splicing. This variant was reported in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome (Lipska et al. 2013. PubMed ID: 23515051; Bruening et al. 1992. PubMed ID: 1302008, reported as 1228+5G>A; Li et al. 2010. PubMed ID: 20442690, reported as IVS9+5G>A). In vitro functional studies indicate that this variant results in defective splicing (Klamt et al. 1998. PubMed ID: 9499425). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
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SpliceAI score (max)
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at