11-32435054-C-G

Variant names:

• chr11-32435054-C-G
• rs1348287926
• NM_024426.6:c.307G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024426.6(WT1):​c.307G>C​(p.Gly103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,314,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G103C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.307G>C	p.Gly103Arg	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.307G>C	p.Gly103Arg	missense	Exon 1 of 10	NP_077742.3
	WT1	NM_001407044.1		c.307G>C	p.Gly103Arg	missense	Exon 1 of 10	NP_001393973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.307G>C	p.Gly103Arg	missense	Exon 1 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.307G>C	p.Gly103Arg	missense	Exon 1 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.307G>C	p.Gly103Arg	missense	Exon 1 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314318 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 646974

African (AFR) AF: 0.00 AC: 0 AN: 25718

American (AMR) AF: 0.00 AC: 0 AN: 23374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21452

East Asian (EAS) AF: 0.00 AC: 0 AN: 30780

South Asian (SAS) AF: 0.00 AC: 0 AN: 69764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3852

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052462

Other (OTH) AF: 0.00 AC: 0 AN: 54558

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G98R variant (also known as c.292G>C), located in coding exon 1 of the WT1 gene, results from a G to C substitution at nucleotide position 292. The glycine at codon 98 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.27	T
PhyloP100		2.1
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Vest4		0.42
MVP		0.63
ClinPred		0.74	D
GERP RS		1.8
PromoterAI		-0.032	Neutral

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: rs1348287926; hg19: chr11-32456600;