11-32388003-A-AACAC

Position:

• chr11-32388003-A-AACAC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_024426.6(WT1):​c.*1054_*1055insGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0086 (0 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: 1.29

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00967 (1417/146578) while in subpopulation NFE AF= 0.0134 (883/65912). AF 95% confidence interval is 0.0127. There are 12 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.*1054_*1055insGTGT		3_prime_UTR_variant	10/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10	c.*1054_*1055insGTGT		3_prime_UTR_variant	10/10	1	NM_024426.6

Frequencies

GnomAD3 genomes AF: 0.00967 AC: 1416 AN: 146462 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00737

Gnomad EAS AF: 0.00100

Gnomad SAS AF: 0.00482

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00864 AC: 713 AN: 82480 Hom.: 0 Cov.: 0 AF XY: 0.00814 AC XY: 310 AN XY: 38080

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.00645

Gnomad4 EAS exome AF: 0.00601

Gnomad4 SAS exome AF: 0.00575

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.00780

GnomAD4 genome AF: 0.00967 AC: 1417 AN: 146578 Hom.: 12 Cov.: 0 AF XY: 0.00922 AC XY: 657 AN XY: 71292

Gnomad4 AFR AF: 0.00258

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00737

Gnomad4 EAS AF: 0.00101

Gnomad4 SAS AF: 0.00482

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.0133

Bravo AF: 0.00818

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

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

- -

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;