11-32392019-C-G

Variant names:

• chr11-32392019-C-G
• rs121907903
• NM_024426.6:c.1400G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_024426.6(WT1):​c.1400G>C​(p.Arg467Pro) 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. R467L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.87
• Publications: 34 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 10 ACMG points.

• PM1: In a hotspot region, there are 12 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 chr11-32392019-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 419332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 11-32392019-C-G is Pathogenic according to our data. Variant chr11-32392019-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.1400G>C	p.Arg467Pro	missense_variant	Exon 9 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1400G>C	p.Arg467Pro	missense_variant	Exon 9 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Drash syndrome Pathogenic:1

May 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

WT1-related disorder Pathogenic:1

Oct 06, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The WT1 c.1385G>C variant is predicted to result in the amino acid substitution p.Arg462Pro. This variant is alternatively referred to as p.Arg394Pro using Legacy nomenclature. It is also referred to as NM_024426.6:c.1400G>C (p.Arg467Pro) using an updated version of this transcript. This variant has been reported in individuals with Denys-Drash syndrome (Fig. 3, Bruening et al. 1992. PubMed ID: 1302008; Table S1, Lehnhardt. 2015. PubMed ID: 25818337). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Alternate nucleotide changes affecting the same amino acid (p.Arg462Gln, p.Arg462Gly, p.Arg462Leu, and p.Arg462Trp) have been reported in individuals with WT1-related disease (Table 1, Pelletier et al. 1991. PubMed ID: 1655284; Jeanpierre et al. 1998. PubMed ID: 9529364; Royer-Pokora et al. 2004. PubMed ID: 15150775; Table 1, Chernin et al. 2010. PubMed ID: 20595692; Table S1, Lehnhardt. 2015. PubMed ID: 25818337). Of note, the alternate p.Arg462Trp (aka p.Arg467Trp) change is reported to be a hotspot variant for Denys-Drash syndrome (Table 6, Lipska-Zietkiewicz et al. 2020. PubMed ID: 32352694). The c.1385G>C (p.Arg462Pro) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;.;.;.
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;.;.;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.95
MVP		0.88
ClinPred		1.0	D
GERP RS		6.0
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121907903; hg19: chr11-32413565; COSMIC: COSV60065800; COSMIC: COSV60065800;