11-32396399-T-C

Position:

• chr11-32396399-T-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.1122A>G​(p.Arg374=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,613,638 control chromosomes in the GnomAD database, including 35,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3587 hom., cov: 32)
  • Exomes 𝑓: 0.18 (32010 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -1.26

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-32396399-T-C is Benign according to our data. Variant chr11-32396399-T-C is described in ClinVar as [Benign]. Clinvar id is 198591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32396399-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.1122A>G	p.Arg374=	synonymous_variant	7/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1122A>G	p.Arg374=	synonymous_variant	7/10	1	NM_024426.6	ENSP00000415516

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27521 AN: 151962 Hom.: 3562 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.243 AC: 61110 AN: 251054 Hom.: 10791 AF XY: 0.243 AC XY: 32918 AN XY: 135708

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.369

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.696

Gnomad SAS exome AF: 0.356

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.180 AC: 263514 AN: 1461558 Hom.: 32010 Cov.: 33 AF XY: 0.185 AC XY: 134187 AN XY: 727068

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.667

Gnomad4 SAS exome AF: 0.352

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.181 AC: 27564 AN: 152080 Hom.: 3587 Cov.: 32 AF XY: 0.193 AC XY: 14309 AN XY: 74332

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.703

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.198

Alfa AF: 0.156 Hom.: 2638

Bravo AF: 0.188

Asia WGS AF: 0.547 AC: 1900 AN: 3478

EpiCase AF: 0.144

EpiControl AF: 0.147

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 48% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 45. Only high quality variants are reported. -
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. -

Wilms tumor 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	- -

Meacham syndrome 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	- -

Nephrotic syndrome, type 4 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2016	Variant summary: The WT1 c.1107A>G (p.Arg369Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 28265/121072 control chromosomes (4959 homozygotes) at a frequency of 0.2334561, which is approximately 24902 times the estimated maximal expected allele frequency of a pathogenic WT1 variant (0.0000094), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

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

- -

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

- -

Drash syndrome;C0950122:Frasier syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.6
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16754; hg19: chr11-32417945; COSMIC: COSV60066333;