rs1554946595

Positions:

• chr11-32435015-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024426.6(WT1):​c.346C>A​(p.Pro116Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,335,946 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P116L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36110932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.346C>A	p.Pro116Thr	missense_variant	1/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10	c.346C>A	p.Pro116Thr	missense_variant	1/10	1	NM_024426.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1335946 Hom.: 0 Cov.: 41 AF XY: 0.00000152 AC XY: 1 AN XY: 657766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000283

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 111 of the WT1 protein (p.Pro111Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 543122). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WT1 protein function. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.331C>A (p.P111T) alteration is located in exon 1 (coding exon 1) of the WT1 gene. This alteration results from a C to A substitution at nucleotide position 331, causing the proline (P) at amino acid position 111 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Drash syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.45	N;N;N;.;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D;D;.;.;.
Sift4G	Benign	0.13	T;T;T;.;.;.
Vest4		0.22
MVP		0.56
ClinPred		0.62	D
GERP RS		2.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554946595; hg19: chr11-32456561;