rs2234585

Positions:

• chr11-32428115-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024426.6(WT1):​c.785-57C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,478,162 control chromosomes in the GnomAD database, including 35,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4535 hom., cov: 33)
  • Exomes 𝑓: 0.18 (31199 hom.)
• Consequence: WT1 NM_024426.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.500

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-32428115-G-A is Benign according to our data. Variant chr11-32428115-G-A is described in ClinVar as [Benign]. Clinvar id is 1292785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32428115-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.785-57C>T		intron_variant		ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.785-57C>T		intron_variant		1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32269 AN: 152062 Hom.: 4505 Cov.: 33

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.184 AC: 244490 AN: 1325982 Hom.: 31199 AF XY: 0.189 AC XY: 122837 AN XY: 650402

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.693

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.214

GnomAD4 genome AF: 0.213 AC: 32340 AN: 152180 Hom.: 4535 Cov.: 33 AF XY: 0.223 AC XY: 16576 AN XY: 74390

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.228

Alfa AF: 0.172 Hom.: 302

Bravo AF: 0.222

Asia WGS AF: 0.581 AC: 2020 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

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 51% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 47. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2234585; hg19: chr11-32449661; COSMIC: COSV60066987;