chr11-32388003-AACACAC-A

Position:

• chr11-32388003-AACACAC-A

Variant summary

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

The NM_024426.6(WT1):​c.*1049_*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 0.226 in 228,348 control chromosomes in the GnomAD database, including 4,603 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4553 hom., cov: 0)
  • Exomes 𝑓: 0.22 (50 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• 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 (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.*1049_*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.*1049_*1054del		3_prime_UTR_variant	10/10	1	NM_024426.6

Frequencies

GnomAD3 genomes AF: 0.231 AC: 33866 AN: 146306 Hom.: 4534 Cov.: 0

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.215 AC: 17632 AN: 81926 Hom.: 50 AF XY: 0.213 AC XY: 8041 AN XY: 37832

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.432

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.232 AC: 33901 AN: 146422 Hom.: 4553 Cov.: 0 AF XY: 0.240 AC XY: 17088 AN XY: 71212

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.244

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephroblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

11p partial monosomy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Meacham syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nephrotic syndrome, type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;