chr11-32392013-T-C

Position:

• chr11-32392013-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_024426.6(WT1):​c.1406A>G​(p.Asp469Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D469N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-32392014-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 11-32392013-T-C is Pathogenic according to our data. Variant chr11-32392013-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3489.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-32392013-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.1406A>G	p.Asp469Gly	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	c.1406A>G	p.Asp469Gly	missense_variant	9/10	1	NM_024426.6	ENSP00000415516

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 28, 2017

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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different missense substitution at this codon (p.Asp464Asn) has been determined to be pathogenic (PMID: 8810912, 5665984, 1655284, 20442690, 22876585, 24379226). This suggests that the aspartic acid residue is critical for WT1 protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported in two individuals affected with WT1-related conditions (PMID: 1655284, 24402088), and was found to be de novo in one of them (PMID: 1655284). This variant is also known as p.Asp396Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 3489). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 464 of the WT1 protein (p.Asp464Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. -

Drash syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 18, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;D;.;.;.;.;.
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;.;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.071	T;D;D;D;D;.;.;.
Sift4G	Benign	0.12	T;T;T;T;T;.;.;.
Polyphen		0.093	B;.;.;.;.;.;.;.
Vest4		0.91
MVP		0.59
ClinPred		0.99	D
GERP RS		6.0
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121907902; hg19: chr11-32413559; COSMIC: COSV60070732; COSMIC: COSV60070732;