rs1554938531

Positions:

• chr11-32389086-T-A
• chr11-32389086-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000452863.10(WT1):​c.1541A>T​(p.Asn514Ile) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N514S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WT1 ENST00000452863.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.1541A>T	p.Asn514Ile	missense_variant	10/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1541A>T	p.Asn514Ile	missense_variant	10/10	1	NM_024426.6	ENSP00000415516

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 01, 2019

This sequence change replaces asparagine with isoleucine at codon 509 of the WT1 protein (p.Asn509Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with WT1-related disease. 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. 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	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;.;D;.;.;.;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.;.;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.68
MVP		0.54
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.91

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: rs1554938531; hg19: chr11-32410632;