Variant 11-32392014-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_024426.6(WT1):c.1405G>A(p.Asp469Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D469G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WT1
NM_024426.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.87

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-32392013-T-C is described in Lovd as [Pathogenic].

PP5

Variant 11-32392014-C-T is Pathogenic according to our data. Variant chr11-32392014-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32392014-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6 linkuse as main transcript	c.1405G>A	p.Asp469Asn	missense_variant	9/10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 linkuse as main transcript	c.1405G>A	p.Asp469Asn	missense_variant	9/10	1	NM_024426.6	ENSP00000415516		P19544-7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 4

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been previously reported as de novo in a similarly affected individual (PMID: 9529364, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with WT1 related disorder (ClinVar ID: VCV000003490, PMID:1655284). A different missense change at the same codon (p.Asp469Gly, p.Asp469Tyr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003489,VCV000547167, PMID:22876585, PMID:1655284, PMID:10738002, PMID:24402088, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.895, PP3_P). A missense variant is a common mechanism associated with Nephrotic syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Drash syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1998

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2023

Published functional studies demonstrate a damaging effect: decreased DNA binding affinity (Pelletier et al, 1991); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.754G>A p.D252N, c.1186G>A p.D396N, and c.1405G>A p.D469N; This variant is associated with the following publications: (PMID: 24379226, 31816618, 1338906, 1655284, 25818337, 29869118, 29294058, 9529364, 9090524, 32891756, 32053599, 34031707, 31328266, 33392118, 25077094, 20442690, Bekheirnia2021[article], 15665984) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;.;D;.;.;.;.;.

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.74

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;.;.;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0030

D;D;D;D;D;.;.;.

Sift4G

Uncertain

0.022

D;D;D;D;D;.;.;.

Polyphen

1.0

D;.;.;.;.;.;.;.

Vest4

0.85

MVP

0.63

ClinPred

1.0

GERP RS

6.0

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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