rs1014605516

Positions:

• chr11-32396379-G-A
• chr11-32396379-G-C
• chr11-32396379-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BS2_Supporting

The NM_024426.6(WT1):​c.1142C>T​(p.Pro381Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.99

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.

• PM1: In a region_of_interest Important for interaction with target DNA (size 14) in uniprot entity WT1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_024426.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• BS2: High AC in GnomAdExome4 at 6 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/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.1142C>T	p.Pro381Leu	missense_variant	7/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1142C>T	p.Pro381Leu	missense_variant	7/10	1	NM_024426.6	ENSP00000415516

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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

Aug 02, 2023

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 543138). This variant has not been reported in the literature in individuals affected with WT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 376 of the WT1 protein (p.Pro376Leu). -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 31, 2021

- -

Wilms tumor 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 24, 2023

This missense variant replaces proline with leucine at codon 376 of the WT1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with WT1-related disorders in the literature. This variant has been identified in 1/31392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;.;.;.;.;.;.;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;.;.;.;.;.;.
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;.;.;.;D
REVEL	Pathogenic	0.70
Sift	Benign	0.031	D;D;T;D;D;.;.;.;D
Sift4G	Uncertain	0.035	D;D;D;D;D;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.;.;.
Vest4		0.52
MVP		0.91
ClinPred		1.0	D
GERP RS		6.2
gMVP		0.75

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: rs1014605516; hg19: chr11-32417925; COSMIC: COSV60078966;