11-32388003-A-AAC

Position:

• chr11-32388003-A-AAC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_024426.6(WT1):​c.*1053_*1054dupGT 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 0.040 (119 hom., cov: 0)
  • Exomes 𝑓: 0.037 (0 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 1.29

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0398 (5828/146512) while in subpopulation AMR AF= 0.0513 (754/14702). AF 95% confidence interval is 0.0483. There are 119 homozygotes in gnomad4. There are 2694 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 5828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.*1053_*1054dupGT		3_prime_UTR_variant	10/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863	c.*1053_*1054dupGT		3_prime_UTR_variant	10/10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 5819 AN: 146396 Hom.: 119 Cov.: 0

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0209

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.0288

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0499

GnomAD4 exome AF: 0.0371 AC: 3052 AN: 82374 Hom.: 0 Cov.: 0 AF XY: 0.0370 AC XY: 1406 AN XY: 38014

Gnomad4 AFR exome AF: 0.0376

Gnomad4 AMR exome AF: 0.0443

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.0483

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0373

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0398 AC: 5828 AN: 146512 Hom.: 119 Cov.: 0 AF XY: 0.0378 AC XY: 2694 AN XY: 71250

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.0513

Gnomad4 ASJ AF: 0.0209

Gnomad4 EAS AF: 0.0243

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0493

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephroblastoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

11p partial monosomy syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Meacham syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Nephrotic syndrome, type 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58549495; hg19: chr11-32409549;