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

Genomes: not found (cov: 32)

Consequence

WT1
NM_024426.6 missense

Scores

10
5
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.87
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 Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-32392019-C-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.864
PP5
Variant 11-32392019-C-G is Pathogenic according to our data. Variant chr11-32392019-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WT1NM_024426.6 linkuse as main transcriptc.1400G>C p.Arg467Pro missense_variant 9/10 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.1400G>C p.Arg467Pro missense_variant 9/101 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:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Drash syndrome Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 1992- -
WT1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 06, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
33
DANN
Uncertain
1.0
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;D;.;.;.;.;.
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.11
T
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-6.2
D;D;D;D;D;.;.;.
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;D;D;D;D;.;.;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;.
Vest4
0.95
MVP
0.88
ClinPred
1.0
D
GERP RS
6.0
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs121907903; hg19: chr11-32413565; COSMIC: COSV60065800; COSMIC: COSV60065800; API