NM_024426.6:c.314C>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_024426.6(WT1):c.314C>G(p.Ala105Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000369 in 1,464,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

WT1
NM_024426.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 3.39

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20041999).

BS2

High AC in GnomAd4 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 link	c.314C>G	p.Ala105Gly	missense_variant	Exon 1 of 10	ENST00000452863.10	NP_077744.4	P19544-7Q6PI38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 link	c.314C>G	p.Ala105Gly	missense_variant	Exon 1 of 10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

62338

Hom.:

AF XY:

0.0000840

AC XY:

AN XY:

35694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000581

Gnomad ASJ exome

AF:

0.000256

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1312324

Hom.:

Cov.:

AF XY:

0.0000310

AC XY:

AN XY:

645788

show subpopulations

Gnomad4 AFR exome

AF:

0.000351

Gnomad4 AMR exome

AF:

0.000435

Gnomad4 ASJ exome

AF:

0.0000471

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000144

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000152

Gnomad4 OTH exome

AF:

0.0000918

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000473

Hom.:

Bravo

AF:

0.0000604

Asia WGS

AF:

0.000289

AC:

AN:

3468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 05, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Aug 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A100G variant (also known as c.299C>G), located in coding exon 1 of the WT1 gene, results from a C to G substitution at nucleotide position 299. The alanine at codon 100 is replaced by glycine, an amino acid with similar properties. This variant was identified in siblings with congenital nephrotic syndrome and both also had a co-occurring variant in NPHS1 (McCarthy HJ et al. Clin J Am Soc Nephrol, 2013 Apr;8:637-48). This variant was also reported in an Algerian patient with disorder of gonadal development (Zidoune H et al. Front Genet, 2022 Aug;13:900574). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Disorder of sexual differentiation

Uncertain:1

Aug 15, 2021

Human Developmental Genetics, Institut Pasteur

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Paternal inheritance -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Drash syndrome

Uncertain:1

Sep 15, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WT1-related disorder

Uncertain:1

Sep 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The WT1 c.299C>G variant is predicted to result in the amino acid substitution p.Ala100Gly. This variant (also described as c.314C>G, p.Ala105Gly in NM_024426.6) has been reported in the homozygous state in a pair of siblings with steroid-resistant nephrotic syndrome (SRNS) who were also apparently homozygous for another missense variant (p.Arg586Gly) in the NPHS1 gene (McCarthy et al. 2013. PubMed ID: 23349334). Of note, both of these individuals were reported to have a more severe phenotype than a third sibling who was also homozygous for the NPHS1 variant but negative for WT1 p.Ala100Gly. The p.Ala100Gly variant has also been observed in the heterozygous state in individuals with various WT1-associated phenotypes including breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596), primary ovarian insufficiency (Table S7, Heddar et al. 2022. PubMed ID: 36099812), and disorders of sex development (DSD) (Zidoune et al. 2022. PubMed ID: 36110220). This variant is reported in 0.058% of alleles in individuals of Latino descent in gnomAD; however, the quality of this data is questionable and should be treated with caution. This variant is interpreted as uncertain by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/476699/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Wilms tumor 1

Uncertain:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.88

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-0.51

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.16

N;N;N;.;.;.

REVEL

Benign

0.22

Sift

Benign

0.32

T;T;T;.;.;.

Sift4G

Benign

0.42

T;T;T;.;.;.

Vest4

0.10

MVP

0.52

ClinPred

0.038

GERP RS

1.9

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over