NM_024426.6:c.1316G>A

Variant names:

• chr11-32392704-C-T
• rs121907901
• NM_024426.6:c.1316G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_024426.6(WT1):​c.1316G>A​(p.Arg439His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R439C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.90
• Publications: 18 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_024426.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-32392705-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• PP5: Variant 11-32392704-C-T is Pathogenic according to our data. Variant chr11-32392704-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.1316G>A	p.Arg439His	missense_variant	Exon 8 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1316G>A	p.Arg439His	missense_variant	Exon 8 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Drash syndrome Pathogenic:2

Jan 01, 2016

Human Genetics Disease in Children – Taif University, Taif University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 15, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:2

Dec 02, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in multiple individuals with Denys Drash syndrome as well as in patients with isolated diffuse mesangial sclerosis or early-onset nephrotic syndrome (Schumacher 1998, Pelletier 1991, Royer-Pokora 2004, Nishi 2019); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also reported as c.1097G>A (R366H); This variant is associated with the following publications: (PMID: 16479084, 26882358, 30963316, 15150775, 9607189, 1655284, 29294058, 1338906, 7645607, 9529364, 11322369, 16932893, 17853480, 15026863, 18203154, 26891727, 21434831, 24402088, 8810912, 27719739, 28780565, 30721404, 31937884, 32604935, 29474669)

Jul 20, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Results on protein functions were inconclusive. 2 de novo cases with parental identity not confirmed. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Pathogenic:1

Jun 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg434 amino acid residue in WT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27300205, 9529364, 7795587, 22172722). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Denys-Drash syndrome and nephrotic syndrome (PMID: 1655284, 26882358, 30721404, 27719739, 30963316). This variant is also known as p.Arg366His in the literature. ClinVar contains an entry for this variant (Variation ID: 3488). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 434 of the WT1 protein (p.Arg434His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.

11p partial monosomy syndrome;C0344542:Aniridia 1;C0345967:Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Pathogenic:1

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nephrotic syndrome, type 4 Pathogenic:1

Oct 14, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 strong

Wilms tumor 1 Pathogenic:1

Jun 11, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Drash syndrome;C0950122:Frasier syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 Pathogenic:1

May 08, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This WT1 variant has been reported in multiple individuals presenting with congenital nephrotic syndrome. A functional study has demonstrated that this variant is associated with a decrease in DNA binding affinity when compared to the wild-type protein. WT1 c.1301G>A is located within one of the four zinc finger regions that are important for protein function. This variant is absent from a large population dataset and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across all species assessed. We consider this variant to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T;.;T;.;.;.;.;.
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;.;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.
Sift4G	Uncertain	0.034	D;T;D;D;D;.;.;.
Vest4		0.84
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.85
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121907901; hg19: chr11-32414250; COSMIC: COSV60065305; COSMIC: COSV60065305;