rs1186470250

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_024426.6(WT1):ā€‹c.133T>Gā€‹(p.Trp45Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,383,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W45R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 0.000013 ( 0 hom. )

Consequence

WT1
NM_024426.6 missense

Scores

4
1
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.24466872).
BS2
High AC in GnomAdExome4 at 18 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WT1NM_024426.6 linkuse as main transcriptc.133T>G p.Trp45Gly missense_variant 1/10 ENST00000452863.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WT1ENST00000452863.10 linkuse as main transcriptc.133T>G p.Trp45Gly missense_variant 1/101 NM_024426.6 P19544-7

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
0.0000130
AC:
18
AN:
1383492
Hom.:
0
Cov.:
44
AF XY:
0.0000147
AC XY:
10
AN XY:
682590
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000158
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 25, 2023In 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 834611). This variant has not been reported in the literature in individuals affected with WT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 40 of the WT1 protein (p.Trp40Gly). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 18, 2022- -
Wilms tumor 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 04, 2023This missense variant replaces tryptophan with glycine at codon 40 in the WT1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with WT1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
22
DANN
Benign
0.95
Eigen
Benign
-0.068
Eigen_PC
Benign
-0.058
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.24
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.80
N;N;N;.;.;.
REVEL
Benign
0.063
Sift
Pathogenic
0.0
D;D;D;.;.;.
Sift4G
Pathogenic
0.0
D;D;T;.;.;.
Vest4
0.52
MutPred
0.31
Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);Loss of MoRF binding (P = 0.0376);
MVP
0.38
ClinPred
0.64
D
GERP RS
2.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1186470250; hg19: chr11-32456774; API