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rs555140661

chr11-32435238-C-Gchr11-32435238-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024426.6(WT1):c.123G>C(p.Pro41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,535,690 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P41P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 30)
Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

WT1
NM_024426.6 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.455
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-32435238-C-G is Benign according to our data. Variant chr11-32435238-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 193453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32435238-C-G is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.455 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0019 (289/152186) while in subpopulation NFE AF= 0.00338 (230/67972). AF 95% confidence interval is 0.00303. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 289 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WT1NM_024426.6 linkuse as main transcriptc.123G>C p.Pro41= synonymous_variant 1/10 ENST00000452863.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WT1ENST00000452863.10 linkuse as main transcriptc.123G>C p.Pro41= synonymous_variant 1/101 NM_024426.6 P19544-7

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00190
AC:
289
AN:
152078
Hom.:
1
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000604
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00338
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00220
AC:
292
AN:
132698
Hom.:
0
AF XY:
0.00233
AC XY:
169
AN XY:
72646
show subpopulations
Gnomad AFR exome
AF:
0.000313
Gnomad AMR exome
AF:
0.000764
Gnomad ASJ exome
AF:
0.00112
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00358
Gnomad FIN exome
AF:
0.000181
Gnomad NFE exome
AF:
0.00344
Gnomad OTH exome
AF:
0.00173
GnomAD4 exome
AF:
0.00304
AC:
4212
AN:
1383504
Hom.:
9
Cov.:
44
AF XY:
0.00310
AC XY:
2113
AN XY:
682680
show subpopulations
Gnomad4 AFR exome
AF:
0.000412
Gnomad4 AMR exome
AF:
0.000912
Gnomad4 ASJ exome
AF:
0.000796
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00349
Gnomad4 FIN exome
AF:
0.000328
Gnomad4 NFE exome
AF:
0.00339
Gnomad4 OTH exome
AF:
0.00281
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00190
AC:
289
AN:
152186
Hom.:
1
Cov.:
30
AF XY:
0.00141
AC XY:
105
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.000602
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00186
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00338
Gnomad4 OTH
AF:
0.00332
Alfa
AF:
0.00144
Hom.:
0
Bravo
AF:
0.00198

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:6
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024WT1: BP4, BP7 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 11, 2022This variant is associated with the following publications: (PMID: 28873162) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 10, 2023- -
not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 06, 2018- -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 01, 2021- -
11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Nephroblastoma Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 20, 2022- -
Meacham syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Wilms tumor 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submittercurationSema4, Sema4Jul 15, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
Cadd
Benign
5.0
Dann
Benign
0.66

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.

Other links and lift over

dbSNP: rs555140661; hg19: chr11-32456784; API