chr11-32396401-G-A

Position:

chr11-32396401-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024426.6(WT1):c.1120C>T(p.Arg374Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R374R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

WT1
NM_024426.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.75

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]

WT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 11-32396401-G-A is Pathogenic according to our data. Variant chr11-32396401-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 449416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32396401-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6 linkuse as main transcript	c.1120C>T	p.Arg374Ter	stop_gained	7/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 linkuse as main transcript	c.1120C>T	p.Arg374Ter	stop_gained	7/10	1	NM_024426.6	ENSP00000415516		P19544-7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 01, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449416). This variant is also known as p.Arg301*. This premature translational stop signal has been observed in individual(s) with Wilms tumors (PMID: 9108089). This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg369*) 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). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2022

The c.1105C>T (p.R369*) alteration, located in exon 7 (coding exon 7) of the WT1 gene, consists of a C to T substitution at nucleotide position 1105. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 369. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (1/31402) total alleles studied. This alteration has been reported de novo in a male patient with bilateral cryptorchidism, nystagmus, mild proteinuria, and Wilms tumor (Terenziani, 2009). Based on the available evidence, this alteration is classified as pathogenic. -

Drash syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

WT1-related Wilms tumor

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 27, 2021

ACMG classification criteria: PVS1, PS4, PM2, PP1 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2017

The R369X variant in the WT1 gene has been reported in at least two individuals with Wilms tumor, one of whom had bilateral disease (Schumacher 1997). The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We interpret R369X as a pathogenic variant. -

WT1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2024

The WT1 c.1105C>T variant is predicted to result in premature protein termination (p.Arg369*). This variant has been reported in individuals with WT1-related disorders (see for example, reported as codon 301 Arg to Stop at Table 2 of Schumacher et al. 1997. PubMed ID: 9108089; p.Arg369Ter in Akramov et al. 2021. PubMed ID: 34106634; p.Q369X in Terenziani et al. 2009. PubMed ID: 19048299). To our knowledge, this variant has not been reported in continental populations in a large population database, indicating this variant is rare. Nonsense variants in WT1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Wilms tumor 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jul 22, 2021

The WT1 c.1054C>T (p.Arg352Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant corresponds to the c.1120C>T (p.Arg374Ter) in the transcript NM_024426.6. This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). It has been reported in the literature in two siblings affected with Wilms tumor, one of whom had bilateral disease, as well as two additional individuals with loss of the wild-type allele in the tumor (PS4; PMID: 9108089, internal data). In summary, this variant meets criteria to be classified as of pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Benign

0.75

MutationTaster

Benign

1.0

A;A

Vest4

0.96

ClinPred

1.0

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over