11-32388003-AACAC-A

Position:

• chr11-32388003-AACAC-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_024426.6(WT1):​c.*1051_*1054del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 228,700 control chromosomes in the GnomAD database, including 2,641 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2633 hom., cov: 0)
  • Exomes 𝑓: 0.10 (8 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:8
• Conservation: PhyloP100: 1.60

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.*1051_*1054del		3_prime_UTR_variant	10/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10	c.*1051_*1054del		3_prime_UTR_variant	10/10	1	NM_024426.6

Frequencies

GnomAD3 genomes AF: 0.163 AC: 23793 AN: 146316 Hom.: 2627 Cov.: 0

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0736

Gnomad MID AF: 0.181

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.102 AC: 8400 AN: 82268 Hom.: 8 AF XY: 0.100 AC XY: 3817 AN XY: 37998

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.0866

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.0159

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0745

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.163 AC: 23823 AN: 146432 Hom.: 2633 Cov.: 0 AF XY: 0.161 AC XY: 11453 AN XY: 71216

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.0736

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, single submitter

Submissions by phenotype

Nephroblastoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

11p partial monosomy syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Meacham syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Nephrotic syndrome, type 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

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: rs58549495; hg19: chr11-32409549;