11-32392014-C-T

Variant names:

• chr11-32392014-C-T
• rs28941778
• NM_024426.6:c.1405G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM5 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.87

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 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 rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.1405G>A	p.Asp469Asn	missense_variant	Exon 9 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1405G>A	p.Asp469Asn	missense_variant	Exon 9 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 4 Pathogenic:2

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D;.;.;.;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
PrimateAI	Pathogenic	0.95	D
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	D
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

Other links and lift over

dbSNP: rs28941778; hg19: chr11-32413560; COSMIC: COSV60066459; COSMIC: COSV60066459;