11-32388003-AACACACACACACACACACAC-AACACACACAC

Variant names:

• chr11-32388003-AACACACACAC-A
• rs58549495
• ENST00000379077.9:n.*1798_*1807delGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_024426.6(WT1):​c.*1045_*1054delGTGTGTGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 229,128 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Denys-Drash syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
• Wilms tumor 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Frasier syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00373 (547/146582) while in subpopulation AFR AF = 0.0113 (454/40230). AF 95% confidence interval is 0.0104. There are 4 homozygotes in GnomAd4. There are 250 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 547 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.*1045_*1054delGTGTGTGTGT		3_prime_UTR_variant	Exon 10 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.*1045_*1054delGTGTGTGTGT		3_prime_UTR_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 540 AN: 146466 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00161

Gnomad SAS AF: 0.000438

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000455

Gnomad OTH AF: 0.00249

GnomAD4 exome AF: 0.00131 AC: 108 AN: 82546 Hom.: 0 AF XY: 0.00126 AC XY: 48 AN XY: 38124

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00926 AC: 36 AN: 3888

American (AMR) AF: 0.00359 AC: 9 AN: 2508

Ashkenazi Jewish (ASJ) AF: 0.00137 AC: 7 AN: 5118

East Asian (EAS) AF: 0.000435 AC: 5 AN: 11482

South Asian (SAS) AF: 0.00 AC: 0 AN: 696

European-Finnish (FIN) AF: 0.00133 AC: 1 AN: 752

Middle Eastern (MID) AF: 0.00204 AC: 1 AN: 490

European-Non Finnish (NFE) AF: 0.000748 AC: 38 AN: 50806

Other (OTH) AF: 0.00162 AC: 11 AN: 6806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00373 AC: 547 AN: 146582 Hom.: 4 Cov.: 0 AF XY: 0.00351 AC XY: 250 AN XY: 71292

African (AFR) AF: 0.0113 AC: 454 AN: 40230

American (AMR) AF: 0.00292 AC: 43 AN: 14716

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3390

East Asian (EAS) AF: 0.00161 AC: 8 AN: 4972

South Asian (SAS) AF: 0.000438 AC: 2 AN: 4562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9592

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000455 AC: 30 AN: 65918

Other (OTH) AF: 0.00246 AC: 5 AN: 2030

Alfa AF: 0.00 Hom.: 53

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58549495; hg19: chr11-32409549;