11-32388003-AACACAC-A

Variant names:

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

Variant summary

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

The NM_024426.6(WT1):​c.*1049_*1054delGTGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 228,348 control chromosomes in the GnomAD database, including 4,603 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4553 hom., cov: 0)
  • Exomes 𝑓: 0.22 (50 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• 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.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.231 AC: 33866 AN: 146306 Hom.: 4534 Cov.: 0

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.215 AC: 17632 AN: 81926 Hom.: 50 AF XY: 0.213 AC XY: 8041 AN XY: 37832

African (AFR) AF: 0.234 AC: 871 AN: 3718

American (AMR) AF: 0.297 AC: 741 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 961 AN: 5066

East Asian (EAS) AF: 0.432 AC: 4956 AN: 11478

South Asian (SAS) AF: 0.348 AC: 240 AN: 690

European-Finnish (FIN) AF: 0.138 AC: 104 AN: 752

Middle Eastern (MID) AF: 0.182 AC: 88 AN: 484

European-Non Finnish (NFE) AF: 0.165 AC: 8316 AN: 50508

Other (OTH) AF: 0.201 AC: 1355 AN: 6736

GnomAD4 genome AF: 0.232 AC: 33901 AN: 146422 Hom.: 4553 Cov.: 0 AF XY: 0.240 AC XY: 17088 AN XY: 71212

African (AFR) AF: 0.227 AC: 9103 AN: 40186

American (AMR) AF: 0.321 AC: 4717 AN: 14698

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 680 AN: 3384

East Asian (EAS) AF: 0.671 AC: 3327 AN: 4960

South Asian (SAS) AF: 0.395 AC: 1801 AN: 4554

European-Finnish (FIN) AF: 0.207 AC: 1984 AN: 9574

Middle Eastern (MID) AF: 0.236 AC: 68 AN: 288

European-Non Finnish (NFE) AF: 0.176 AC: 11597 AN: 65868

Other (OTH) AF: 0.244 AC: 495 AN: 2026

Alfa AF: 0.0848 Hom.: 53

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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

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; COSMIC: COSV60065421; COSMIC: COSV60065421;