rs2234583

Variant names:

• chr11-32434752-G-A
• rs2234583
• NM_024426.6:c.609C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32434752-G-A
• chr11-32434752-G-C
• chr11-32434752-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024426.6(WT1):​c.609C>T​(p.Asn203Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0766 in 1,612,768 control chromosomes in the GnomAD database, including 6,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1987 hom., cov: 33)
  • Exomes 𝑓: 0.071 (4870 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.877

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 11-32434752-G-A is Benign according to our data. Variant chr11-32434752-G-A is described in ClinVar as [Benign]. Clinvar id is 261713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32434752-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.877 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.609C>T	p.Asn203Asn	synonymous_variant	Exon 1 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.609C>T	p.Asn203Asn	synonymous_variant	Exon 1 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19344 AN: 152174 Hom.: 1987 Cov.: 33

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0817

Gnomad ASJ AF: 0.0730

Gnomad EAS AF: 0.00963

Gnomad SAS AF: 0.0683

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0692

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.0755 AC: 18488 AN: 244874 Hom.: 1163 AF XY: 0.0725 AC XY: 9695 AN XY: 133792

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.0868

Gnomad EAS exome AF: 0.00253

Gnomad SAS exome AF: 0.0750

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0744

GnomAD4 exome AF: 0.0713 AC: 104150 AN: 1460478 Hom.: 4870 Cov.: 43 AF XY: 0.0713 AC XY: 51825 AN XY: 726566

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.0857

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.0791

Gnomad4 FIN exome AF: 0.0527

Gnomad4 NFE exome AF: 0.0663

Gnomad4 OTH exome AF: 0.0800

GnomAD4 genome AF: 0.127 AC: 19370 AN: 152290 Hom.: 1987 Cov.: 33 AF XY: 0.125 AC XY: 9332 AN XY: 74466

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.0816

Gnomad4 ASJ AF: 0.0730

Gnomad4 EAS AF: 0.00966

Gnomad4 SAS AF: 0.0683

Gnomad4 FIN AF: 0.0551

Gnomad4 NFE AF: 0.0692

Gnomad4 OTH AF: 0.113

Alfa AF: 0.0992 Hom.: 658

Bravo AF: 0.134

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.0727

EpiControl AF: 0.0729

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 24, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wilms tumor 1 Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meacham syndrome Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 4 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 26, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The WT1 c.594C>T (p.Asn198Asn) 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 along with 4/5 in silico splice prediction tools predicting the variant not to have an impact on splicing. This variant was found in 9132/113272 control chromosomes (598 homozygotes), predominantly observed in the African subpopulation (366 homozygotes) at a frequency of 0.2917204 (2713/9300). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic WT1 variant (0.0000094), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Taken together, this variant is classified as Benign. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Oct 28, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frasier syndrome Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Drash syndrome Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WT1-related disorder Benign:1

Jun 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.4
DANN	Benign	0.97

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: rs2234583; hg19: chr11-32456298; COSMIC: COSV60069793; COSMIC: COSV60069793;