rs2234582

Positions:

• chr11-32435148-C-A
• chr11-32435148-C-T

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.213G>T​(p.Pro71Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,517,410 control chromosomes in the GnomAD database, including 49,299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9730 hom., cov: 31)
  • Exomes 𝑓: 0.23 (39569 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.0700

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=-0.67).
• BP6: Variant 11-32435148-C-A is Benign according to our data. Variant chr11-32435148-C-A is described in ClinVar as [Benign]. Clinvar id is 261710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32435148-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.213G>T	p.Pro71Pro	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.213G>T	p.Pro71Pro	synonymous_variant	1/10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46763 AN: 151664 Hom.: 9719 Cov.: 31

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.0826

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.311

GnomAD3 exomes AF: 0.220 AC: 25574 AN: 116068 Hom.: 3558 AF XY: 0.228 AC XY: 14662 AN XY: 64184

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.0637

Gnomad SAS exome AF: 0.304

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.229 AC: 312903 AN: 1365640 Hom.: 39569 Cov.: 52 AF XY: 0.231 AC XY: 155556 AN XY: 673178

Gnomad4 AFR exome AF: 0.609

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.0807

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.308 AC: 46815 AN: 151770 Hom.: 9730 Cov.: 31 AF XY: 0.301 AC XY: 22361 AN XY: 74180

Gnomad4 AFR AF: 0.591

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.0680

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.313

Alfa AF: 0.262 Hom.: 1176

Bravo AF: 0.321

Asia WGS AF: 0.228 AC: 787 AN: 3452

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 23. Only high quality variants are reported. -
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 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 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	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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 12, 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	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2016	Variant summary: The WT1 c.198G>T (p.Pro66Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3159/9576 control chromosomes (520 homozygotes) at a frequency of 0.3298872, which is approximately 35188 times the estimated maximal expected allele frequency of a pathogenic WT1 variant (0.0000094), suggesting this variant is a benign polymorphism. Additionally, one clinical lab has classified this variant as benign. Taken together and based on the high allele frequency in the general population, this variant was 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	-0.67
CADD	Benign	9.2
DANN	Benign	0.85

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: rs2234582; hg19: chr11-32456694; COSMIC: COSV60067015; COSMIC: COSV60067015;