11-32392704-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_024426.6(WT1):c.1316G>A(p.Arg439His) 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. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
WT1
NM_024426.6 missense
NM_024426.6 missense
Scores
9
3
4
Clinical Significance
Conservation
PhyloP100: 7.90
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.792
PP5
Variant 11-32392704-C-T is Pathogenic according to our data. Variant chr11-32392704-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32392704-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WT1 | NM_024426.6 | c.1316G>A | p.Arg439His | missense_variant | 8/10 | ENST00000452863.10 | NP_077744.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WT1 | ENST00000452863.10 | c.1316G>A | p.Arg439His | missense_variant | 8/10 | 1 | NM_024426.6 | ENSP00000415516.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Drash syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Human Genetics Disease in Children – Taif University, Taif University | Jan 01, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 15, 2008 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 20, 2020 | Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Results on protein functions were inconclusive. 2 de novo cases with parental identity not confirmed. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2021 | Identified in multiple individuals with Denys Drash syndrome as well as in patients with isolated diffuse mesangial sclerosis or early-onset nephrotic syndrome (Schumacher 1998, Pelletier 1991, Royer-Pokora 2004, Nishi 2019); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also reported as c.1097G>A (R366H); This variant is associated with the following publications: (PMID: 16479084, 26882358, 30963316, 15150775, 9607189, 1655284, 29294058, 1338906, 7645607, 9529364, 11322369, 16932893, 17853480, 15026863, 18203154, 26891727, 21434831, 24402088, 8810912, 27719739, 28780565, 30721404, 31937884, 32604935, 29474669) - |
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 | Jun 15, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg434 amino acid residue in WT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27300205, 9529364, 7795587, 22172722). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Denys-Drash syndrome and nephrotic syndrome (PMID: 1655284, 26882358, 30721404, 27719739, 30963316). This variant is also known as p.Arg366His in the literature. ClinVar contains an entry for this variant (Variation ID: 3488). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 434 of the WT1 protein (p.Arg434His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. - |
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 | Jan 17, 2022 | - - |
Nephrotic syndrome, type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 14, 2021 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong - |
Wilms tumor 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 11, 2021 | - - |
Drash syndrome;C0950122:Frasier syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 08, 2020 | This WT1 variant has been reported in multiple individuals presenting with congenital nephrotic syndrome. A functional study has demonstrated that this variant is associated with a decrease in DNA binding affinity when compared to the wild-type protein. WT1 c.1301G>A is located within one of the four zinc finger regions that are important for protein function. This variant is absent from a large population dataset and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across all species assessed. We consider this variant to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T;.;.;.;.;.
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Benign
T
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D;.;.;.
Sift4G
Uncertain
D;T;D;D;D;.;.;.
Polyphen
D;.;.;.;.;.;.;.
Vest4
MVP
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at