Variant rs776155094 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_024426.6(WT1):c.151del(p.Ala51ProfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000391 in 1,533,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A51A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

WT1
NM_024426.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 0.811

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6 linkuse as main transcript	c.151del	p.Ala51ProfsTer31	frameshift_variant	1/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10 linkuse as main transcript	c.151del	p.Ala51ProfsTer31	frameshift_variant	1/10	1	NM_024426.6		P19544-7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000762

AC:

AN:

131284

Hom.:

AF XY:

0.00

AC XY:

AN XY:

71976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000202

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1380958

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

681070

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:

0.00000278

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Precursor B-cell acute lymphoblastic leukemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 16, 2016

This is a frameshift variant, in which a G is deleted at coding position 136 and is predicted to change an Alanine to a Proline and shift the reading frame. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change creates a premature translational stop signal (p.Ala46Profs*31) in the WT1 gene. It is unclear whether it will result in an absent or disrupted protein product because a major initiation site located at codon 69 has the potential to rescue this variant. This variant is present in population databases (rs776155094, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with anaplastic astrocytoma (PMID: 31970404). ClinVar contains an entry for this variant (Variation ID: 265295). Downstream of the non-canonical translation start site (CTG) at codon 1, the nearest methionine codon that can be used to initiate translation of the WT1 protein lies at codon 69. This downstream in-frame ATG is known as a major initiation site (PMID: 28811308, 16987884, 8621495). The functional significance of the different WT1 protein isoforms is unknown (PMID: 8621495), however mice lacking the N-terminal 68 amino acids develop normally and are fertile (PMID: 12640141). Based on these results, the impact of this variant on WT1 protein function is uncertain. In 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. -

Drash syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 03, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2023

Nonsense variant predicted to result in protein truncation; however a downstream in-frame ATG could serve as an alternate initiator codon which may result in a smaller, yet still functional, protein (Bruenig et al., 1996; Scharnhorst et al., 1999; Yang et al., 2007).; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with pancreatic cancer and pediatric glioma (Skaro et al., 2019; Muskens et al., 2020); Also known as c.151del/p.(A51Pfs*31); This variant is associated with the following publications: (PMID: 26633542, 30665703, 31970404, 30716324, 8621495, 10438524, 17361230) -

WT1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 29, 2024

The WT1 c.136delG variant is predicted to result in a frameshift and premature protein termination (p.Ala46Profs*31). This variant has been reported in an individual with anaplastic astrocytoma (Muskens et al. 2020. PubMed ID: 31970404) and another individual with intraductal papillary mucinous neoplasms (IPMNs) at risk for developing pancreatic cancer (Skaro et al. 2019. PubMed ID: 30716324), but it has not been reported in patients with established WT-related disorders. This variant would typically be expected to cause a frameshift leading to premature termination; however there is a downstream, in-frame methionine residue (p.Met69) that has been shown to act as an alternate initiation site and potentially rescue WT1 translation (Bruening and Pelletier. 1996. PubMed ID: 8621495; Scharnhorst et al. 1999. PubMed ID: 10438524). Furthermore, significant N-terminal variation has been observed in functional WT1 isoforms (same studies), and a mouse model lacking the 68 N-terminal amino acids developed normally and remained capable of reproduction (Miles et al. 2003. PubMed ID: 12640141). This variant is reported in 0.0020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/265295/). Taken together, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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