rs1799937

Variant names:

• chr11-32389228-A-G
• rs1799937
• NM_024426.6:c.1448-49T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024426.6(WT1):​c.1448-49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,612,978 control chromosomes in the GnomAD database, including 75,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11403 hom., cov: 32)
  • Exomes 𝑓: 0.27 (64340 hom.)
• Consequence: WT1 NM_024426.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.842
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-32389228-A-G is Benign according to our data. Variant chr11-32389228-A-G is described in ClinVar as Benign. ClinVar VariationId is 261709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.1448-49T>C		intron_variant	Intron 9 of 9	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1448-49T>C		intron_variant	Intron 9 of 9	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53974 AN: 151906 Hom.: 11372 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.359

GnomAD2 exomes AF: 0.349 AC: 87480 AN: 250408 AF XY: 0.346

Gnomad AFR exome AF: 0.532

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.722

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.275 AC: 401202 AN: 1460954 Hom.: 64340 Cov.: 33 AF XY: 0.279 AC XY: 202853 AN XY: 726788

African (AFR) AF: 0.533 AC: 17845 AN: 33460

American (AMR) AF: 0.427 AC: 19063 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8729 AN: 26126

East Asian (EAS) AF: 0.686 AC: 27208 AN: 39686

South Asian (SAS) AF: 0.479 AC: 41261 AN: 86214

European-Finnish (FIN) AF: 0.217 AC: 11533 AN: 53212

Middle Eastern (MID) AF: 0.349 AC: 2007 AN: 5758

European-Non Finnish (NFE) AF: 0.229 AC: 254620 AN: 1111472

Other (OTH) AF: 0.314 AC: 18936 AN: 60346

GnomAD4 genome AF: 0.355 AC: 54044 AN: 152024 Hom.: 11403 Cov.: 32 AF XY: 0.363 AC XY: 26948 AN XY: 74306

African (AFR) AF: 0.523 AC: 21660 AN: 41422

American (AMR) AF: 0.395 AC: 6042 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1129 AN: 3470

East Asian (EAS) AF: 0.725 AC: 3748 AN: 5168

South Asian (SAS) AF: 0.506 AC: 2430 AN: 4802

European-Finnish (FIN) AF: 0.222 AC: 2355 AN: 10600

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15590 AN: 67962

Other (OTH) AF: 0.368 AC: 776 AN: 2110

Alfa AF: 0.323 Hom.: 2543

Bravo AF: 0.376

Asia WGS AF: 0.632 AC: 2198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 58% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 54. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Wilms tumor 1 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frasier syndrome Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meacham syndrome Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 4 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Drash syndrome Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0050
DANN	Benign	0.44
PhyloP100		-0.84
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: rs1799937; hg19: chr11-32410774; COSMIC: COSV60066949;