11-32392704-C-T

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

Scores

9
3
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.90
Variant links:
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
WT1NM_024426.6 linkuse as main transcriptc.1316G>A p.Arg439His missense_variant 8/10 ENST00000452863.10 NP_077744.4 P19544-7Q6PI38

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WT1ENST00000452863.10 linkuse as main transcriptc.1316G>A p.Arg439His missense_variant 8/101 NM_024426.6 ENSP00000415516.5 P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
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 providedclinical testingHuman Genetics Disease in Children – Taif University, Taif UniversityJan 01, 2016- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 15, 2008- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJul 20, 2020Not 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 submitterclinical testingGeneDxDec 02, 2021Identified 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 15, 2021For 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 17, 2022- -
Nephrotic syndrome, type 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinOct 14, 2021ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong -
Wilms tumor 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJun 11, 2021- -
Drash syndrome;C0950122:Frasier syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityMay 08, 2020This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
33
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.69
T;.;T;.;.;.;.;.
M_CAP
Benign
0.039
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.87
T
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-4.6
D;D;D;D;D;.;.;.
REVEL
Uncertain
0.51
Sift
Pathogenic
0.0
D;D;D;D;D;.;.;.
Sift4G
Uncertain
0.034
D;T;D;D;D;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;.
Vest4
0.84
MVP
0.47
ClinPred
1.0
D
GERP RS
5.7
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121907901; hg19: chr11-32414250; COSMIC: COSV60065305; COSMIC: COSV60065305; API