11-32388003-AACACACACACACACACACAC-AACACACACACAC

Variant names:

• chr11-32388003-AACACACAC-A
• rs58549495
• ENST00000379077.9:n.*1800_*1807delGTGTGTGT

Variant summary

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

The NM_024426.6(WT1):​c.*1047_*1054delGTGTGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 225,564 control chromosomes in the GnomAD database, including 78 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (76 hom., cov: 0)
  • Exomes 𝑓: 0.055 (2 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 amr. GnomAd4 allele frequency = 0.0296 (4331/146500) while in subpopulation AMR AF = 0.0374 (550/14700). AF 95% confidence interval is 0.0353. There are 76 homozygotes in GnomAd4. There are 2044 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.*1047_*1054delGTGTGTGT		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.*1047_*1054delGTGTGTGT		3_prime_UTR_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4327 AN: 146388 Hom.: 76 Cov.: 0

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.0305

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0438

GnomAD4 exome AF: 0.0555 AC: 4385 AN: 79064 Hom.: 2 AF XY: 0.0535 AC XY: 1960 AN XY: 36652

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

African (AFR) AF: 0.0431 AC: 164 AN: 3804

American (AMR) AF: 0.0723 AC: 171 AN: 2366

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 318 AN: 5002

East Asian (EAS) AF: 0.128 AC: 1188 AN: 9288

South Asian (SAS) AF: 0.0271 AC: 17 AN: 628

European-Finnish (FIN) AF: 0.0420 AC: 31 AN: 738

Middle Eastern (MID) AF: 0.0519 AC: 25 AN: 482

European-Non Finnish (NFE) AF: 0.0426 AC: 2138 AN: 50136

Other (OTH) AF: 0.0503 AC: 333 AN: 6620

⚠️ 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: 0.0296 AC: 4331 AN: 146500 Hom.: 76 Cov.: 0 AF XY: 0.0287 AC XY: 2044 AN XY: 71242

African (AFR) AF: 0.0205 AC: 826 AN: 40222

American (AMR) AF: 0.0374 AC: 550 AN: 14700

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 178 AN: 3390

East Asian (EAS) AF: 0.0121 AC: 60 AN: 4960

South Asian (SAS) AF: 0.00723 AC: 33 AN: 4562

European-Finnish (FIN) AF: 0.0156 AC: 149 AN: 9576

Middle Eastern (MID) AF: 0.0451 AC: 13 AN: 288

European-Non Finnish (NFE) AF: 0.0365 AC: 2407 AN: 65890

Other (OTH) AF: 0.0434 AC: 88 AN: 2028

Alfa AF: 0.0105 Hom.: 53

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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;