rs121907906

Positions:

• chr11-32392717-G-A
• chr11-32392717-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024426.6(WT1):​c.1303C>T​(p.Arg435Ter) variant causes a stop gained change involving the alteration of a non-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 (★★). Synonymous variant affecting the same amino acid position (i.e. R435R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 NM_024426.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-32392717-G-A is Pathogenic according to our data. Variant chr11-32392717-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32392717-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.1303C>T	p.Arg435Ter	stop_gained	8/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10	c.1303C>T	p.Arg435Ter	stop_gained	8/10	1	NM_024426.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in individuals with personal history consistent with pathogenic variants in this gene (Kaplinsky et al., 1996; Kohler et al., 2011; Lehnhardt et al., 2015); This variant is associated with the following publications: (PMID: 25525159, 21508141, 23515051, 20106868, 9090524, 25818337, 8411073, 34308104, 36496321, 8975729) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Wilms tumor 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 27, 2021	- -

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 30, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3497). This variant is also known as p.Arg362*. This premature translational stop signal has been observed in individuals with Wilms tumor (PMID: 8975729, 20106868, 21508141, 23515051, 25818337). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg430*) in the WT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WT1 are known to be pathogenic (PMID: 15150775). -

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

Oct 31, 2018

- -

Drash syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs121907906; hg19: chr11-32414263; COSMIC: COSV60068301; COSMIC: COSV60068301;