11-32435335-G-C

Variant names:

• chr11-32435335-G-C
• rs948132360
• NM_024426.6:c.26C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_024426.6(WT1):​c.26C>G​(p.Pro9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000797 in 1,380,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P9A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11
• Publications: 1 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-AS (HGNC:18135): (WT1 antisense RNA) This gene is located upstream of the Wilms tumor 1 (WT1) gene; these two genes are bi-directionally transcribed from the same promoter region. This gene is imprinted in kidney, with preferential expression from the paternal allele. Imprinting defects at chromosome 11p13 may contribute to tumorigenesis. [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20159772).
• BP6: Variant 11-32435335-G-C is Benign according to our data. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272. Variant chr11-32435335-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 569272.
• BS2: High AC in GnomAdExome4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.26C>G	p.Pro9Arg	missense_variant	Exon 1 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.26C>G	p.Pro9Arg	missense_variant	Exon 1 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000797 AC: 11 AN: 1380650 Hom.: 0 Cov.: 44 AF XY: 0.00000734 AC XY: 5 AN XY: 681142

African (AFR) AF: 0.00 AC: 0 AN: 31496

American (AMR) AF: 0.00 AC: 0 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25152

East Asian (EAS) AF: 0.00 AC: 0 AN: 35696

South Asian (SAS) AF: 0.00 AC: 0 AN: 79118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1078266

Other (OTH) AF: 0.00 AC: 0 AN: 57686

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4 of the WT1 protein (p.Pro4Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gonadal failure (PMID: 30668521). ClinVar contains an entry for this variant (Variation ID: 569272). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
PhyloP100		4.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.70	N;N;N;.;.;.
REVEL	Benign	0.088
Sift	Uncertain	0.0010	D;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.
Vest4		0.30
MutPred		0.14		Loss of glycosylation at S6 (P = 0.0477);Loss of glycosylation at S6 (P = 0.0477);Loss of glycosylation at S6 (P = 0.0477);Loss of glycosylation at S6 (P = 0.0477);Loss of glycosylation at S6 (P = 0.0477);Loss of glycosylation at S6 (P = 0.0477);
MVP		0.42
ClinPred		0.89	D
GERP RS		3.0
PromoterAI		0.0031	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: rs948132360; hg19: chr11-32456881;