11-32388003-AACACACACACACACACACAC-AACACACACACACACACACACACAC

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_024426.6(WT1):​c.*1051_*1054dupGTGT 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
• 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: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1417 AD gene.

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_*1054dupGTGT		3_prime_UTR	Exon 10 of 10	NP_077744.4
	WT1	NM_024424.5		c.*1051_*1054dupGTGT		3_prime_UTR	Exon 10 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.*1051_*1054dupGTGT		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_*1054dupGTGT		3_prime_UTR	Exon 10 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.*1051_*1054dupGTGT		3_prime_UTR	Exon 9 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.*1051_*1054dupGTGT		3_prime_UTR	Exon 9 of 9	ENSP00000331327.5	J3KNN9

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

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

African (AFR) AF: 0.00257 AC: 10 AN: 3892

American (AMR) AF: 0.0120 AC: 30 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.00645 AC: 33 AN: 5114

East Asian (EAS) AF: 0.00601 AC: 69 AN: 11486

South Asian (SAS) AF: 0.00575 AC: 4 AN: 696

European-Finnish (FIN) AF: 0.0213 AC: 16 AN: 750

Middle Eastern (MID) AF: 0.00813 AC: 4 AN: 492

European-Non Finnish (NFE) AF: 0.00973 AC: 494 AN: 50750

Other (OTH) AF: 0.00780 AC: 53 AN: 6798

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

African (AFR) AF: 0.00258 AC: 104 AN: 40234

American (AMR) AF: 0.0112 AC: 165 AN: 14718

Ashkenazi Jewish (ASJ) AF: 0.00737 AC: 25 AN: 3390

East Asian (EAS) AF: 0.00101 AC: 5 AN: 4972

South Asian (SAS) AF: 0.00482 AC: 22 AN: 4562

European-Finnish (FIN) AF: 0.0194 AC: 186 AN: 9588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0134 AC: 883 AN: 65912

Other (OTH) AF: 0.0133 AC: 27 AN: 2030

Alfa AF: 0.0232 Hom.: 53

Bravo AF: 0.00818

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	11p partial monosomy syndrome (1)
-	1	-	Meacham syndrome (1)
-	1	-	Nephroblastoma (1)
-	1	-	Nephrotic syndrome, type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
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;