chr11-32417492-T-C

Variant names:

• chr11-32417492-T-C
• rs2295081
• NM_024426.6:c.965+85A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024426.6(WT1):​c.965+85A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,265,104 control chromosomes in the GnomAD database, including 62,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10598 hom., cov: 32)
  • Exomes 𝑓: 0.28 (51410 hom.)
• Consequence: WT1 NM_024426.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.70

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-32417492-T-C is Benign according to our data. Variant chr11-32417492-T-C is described in ClinVar as [Benign]. Clinvar id is 1226513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32417492-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.965+85A>G		intron_variant	Intron 4 of 9	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.965+85A>G		intron_variant	Intron 4 of 9	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52446 AN: 151934 Hom.: 10564 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.279 AC: 310620 AN: 1113052 Hom.: 51410 Cov.: 15 AF XY: 0.285 AC XY: 161927 AN XY: 568508

Gnomad4 AFR exome AF: 0.489 AC: 12652 AN: 25896

Gnomad4 AMR exome AF: 0.426 AC: 17833 AN: 41860

Gnomad4 ASJ exome AF: 0.341 AC: 8128 AN: 23806

Gnomad4 EAS exome AF: 0.685 AC: 25511 AN: 37242

Gnomad4 SAS exome AF: 0.484 AC: 37050 AN: 76522

Gnomad4 FIN exome AF: 0.216 AC: 11202 AN: 51958

Gnomad4 NFE exome AF: 0.226 AC: 181236 AN: 801972

Gnomad4 Remaining exome AF: 0.312 AC: 15217 AN: 48702

GnomAD4 genome AF: 0.345 AC: 52523 AN: 152052 Hom.: 10598 Cov.: 32 AF XY: 0.353 AC XY: 26215 AN XY: 74336

Gnomad4 AFR AF: 0.485 AC: 0.485254 AN: 0.485254

Gnomad4 AMR AF: 0.396 AC: 0.396035 AN: 0.396035

Gnomad4 ASJ AF: 0.330 AC: 0.330069 AN: 0.330069

Gnomad4 EAS AF: 0.724 AC: 0.724304 AN: 0.724304

Gnomad4 SAS AF: 0.512 AC: 0.511638 AN: 0.511638

Gnomad4 FIN AF: 0.220 AC: 0.2196 AN: 0.2196

Gnomad4 NFE AF: 0.230 AC: 0.229533 AN: 0.229533

Gnomad4 OTH AF: 0.363 AC: 0.363292 AN: 0.363292

Alfa AF: 0.290 Hom.: 984

Bravo AF: 0.364

Asia WGS AF: 0.635 AC: 2206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 57% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 53. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.29
DANN	Benign	0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs2295081; hg19: chr11-32439038; COSMIC: COSV60068824;