11-32388003-AACACACACACACACACACAC-AACACACACACACACAC

Variant names:

• chr11-32388003-AACAC-A
• rs58549495
• NM_024426.6:c.*1051_*1054delGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_024426.6(WT1):​c.*1051_*1054delGTGT 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
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024426.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.*1051_*1054delGTGT		3_prime_UTR	Exon 10 of 10	NP_077744.4
	WT1	NM_024424.5		c.*1051_*1054delGTGT		3_prime_UTR	Exon 10 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.*1051_*1054delGTGT		3_prime_UTR	Exon 10 of 10	NP_001393973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.*1051_*1054delGTGT		3_prime_UTR	Exon 10 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.*1051_*1054delGTGT		3_prime_UTR	Exon 9 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.*1051_*1054delGTGT		3_prime_UTR	Exon 9 of 9	ENSP00000331327.5	J3KNN9

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

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

African (AFR) AF: 0.261 AC: 1006 AN: 3852

American (AMR) AF: 0.0866 AC: 217 AN: 2506

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 622 AN: 5110

East Asian (EAS) AF: 0.0159 AC: 182 AN: 11482

South Asian (SAS) AF: 0.123 AC: 85 AN: 690

European-Finnish (FIN) AF: 0.0745 AC: 56 AN: 752

Middle Eastern (MID) AF: 0.142 AC: 70 AN: 492

European-Non Finnish (NFE) AF: 0.106 AC: 5378 AN: 50608

Other (OTH) AF: 0.116 AC: 784 AN: 6776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.319 AC: 12822 AN: 40180

American (AMR) AF: 0.107 AC: 1567 AN: 14702

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 424 AN: 3386

East Asian (EAS) AF: 0.0282 AC: 140 AN: 4970

South Asian (SAS) AF: 0.131 AC: 596 AN: 4550

European-Finnish (FIN) AF: 0.0736 AC: 705 AN: 9574

Middle Eastern (MID) AF: 0.164 AC: 47 AN: 286

European-Non Finnish (NFE) AF: 0.108 AC: 7120 AN: 65872

Other (OTH) AF: 0.151 AC: 306 AN: 2028

Alfa AF: 0.0500 Hom.: 53

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	11p partial monosomy syndrome (2)
-	2	-	Meacham syndrome (2)
-	2	-	Nephroblastoma (2)
-	2	-	Nephrotic syndrome, type 4 (2)

Computational scores

Source: dbNSFP v4.9

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

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

Other links and lift over

dbSNP: rs58549495; hg19: chr11-32409549; COSMIC: COSV60070263; COSMIC: COSV60070263;