rs1799925

Positions:

• chr11-32435016-G-A
• chr11-32435016-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024426.6(WT1):​c.345C>T​(p.Pro115Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,485,642 control chromosomes in the GnomAD database, including 29,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3347 hom., cov: 33)
  • Exomes 𝑓: 0.17 (26154 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 1.31

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-32435016-G-A is Benign according to our data. Variant chr11-32435016-G-A is described in ClinVar as [Benign]. Clinvar id is 193454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32435016-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.345C>T	p.Pro115Pro	synonymous_variant	1/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.345C>T	p.Pro115Pro	synonymous_variant	1/10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25530 AN: 151800 Hom.: 3334 Cov.: 33

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.274 AC: 22949 AN: 83840 Hom.: 4465 AF XY: 0.272 AC XY: 12660 AN XY: 46480

Gnomad AFR exome AF: 0.0776

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.691

Gnomad SAS exome AF: 0.348

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.170 AC: 226403 AN: 1333734 Hom.: 26154 Cov.: 53 AF XY: 0.173 AC XY: 113905 AN XY: 656528

Gnomad4 AFR exome AF: 0.0635

Gnomad4 AMR exome AF: 0.352

Gnomad4 ASJ exome AF: 0.160

Gnomad4 EAS exome AF: 0.662

Gnomad4 SAS exome AF: 0.325

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.194

GnomAD4 genome AF: 0.168 AC: 25559 AN: 151908 Hom.: 3347 Cov.: 33 AF XY: 0.179 AC XY: 13322 AN XY: 74266

Gnomad4 AFR AF: 0.0681

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.685

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.191

Alfa AF: 0.141 Hom.: 440

Bravo AF: 0.173

Asia WGS AF: 0.477 AC: 1647 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 43. Only high quality variants are reported. -

Wilms tumor 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Meacham syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephrotic syndrome, type 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2016	Variant summary: The WT1 c.330C>T (p.Pro110Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing and ESE finder predicting effects on ESE binding sites. This variant was found in the large, broad control population, ExAC, with an allele frequency of 1620/4996 (285 homozygotes, 1/3, frequency: 0.3242594), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic WT1 variant of 1/106382 (0.0000094), suggesting this variant is likely a benign polymorphism. In addition, a reputable clinical laboratory cites the variant as "benign." Therefore, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nephroblastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 28, 2019

- -

Frasier syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Drash syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.96

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

Other links and lift over

dbSNP: rs1799925; hg19: chr11-32456562;