chr11-32388003-A-AACACAC

Variant names:

• chr11-32388003-A-AACACAC
• rs58549495
• ENST00000379077.9:n.*1802_*1807dupGTGTGT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_024426.6(WT1):​c.*1049_*1054dupGTGTGT 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 0.00023 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00012 (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: 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: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAd4 at 34 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.*1049_*1054dupGTGTGT		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.*1049_*1054dupGTGTGT		3_prime_UTR_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 33 AN: 146470 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000408

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000401

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000273

Gnomad OTH AF: 0.000498

GnomAD4 exome AF: 0.000121 AC: 10 AN: 82616 Hom.: 0 Cov.: 0 AF XY: 0.000131 AC XY: 5 AN XY: 38144

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

African (AFR) AF: 0.00 AC: 0 AN: 3892

American (AMR) AF: 0.00119 AC: 3 AN: 2512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5124

East Asian (EAS) AF: 0.000174 AC: 2 AN: 11494

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.0000983 AC: 5 AN: 50846

Other (OTH) AF: 0.00 AC: 0 AN: 6808

⚠️ 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: 0.000232 AC: 34 AN: 146586 Hom.: 0 Cov.: 0 AF XY: 0.000210 AC XY: 15 AN XY: 71296

African (AFR) AF: 0.000149 AC: 6 AN: 40234

American (AMR) AF: 0.000408 AC: 6 AN: 14716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.000402 AC: 2 AN: 4972

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4562

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

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

European-Non Finnish (NFE) AF: 0.000273 AC: 18 AN: 65918

Other (OTH) AF: 0.000493 AC: 1 AN: 2030

Alfa AF: 0.00 Hom.: 53

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

Submissions by phenotype

Nephroblastoma Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

11p partial monosomy syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meacham syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 4 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

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;