rs121907903

Positions:

• chr11-32392019-C-A
• chr11-32392019-C-G
• chr11-32392019-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The ENST00000452863.10(WT1):​c.1400G>T​(p.Arg467Leu) 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. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 ENST00000452863.10 missense
• Clinical Significance: - - O:1
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000452863.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-32392019-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.1400G>T	p.Arg467Leu	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.1400G>T	p.Arg467Leu	missense_variant	9/10	1	NM_024426.6	ENSP00000415516

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Acute myeloid leukemia Other:1

-, no assertion criteria provided

clinical testing

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Jan 24, 2024

This variant was detected in a relapsed acute myeloid leukemia patient as a somatic mutation accompanied by a AKAP9::PDGFRA translocation. This variant is similar to WT1 p.Arg467Pro, which also substitutes a non-polar amino acid for the charged polar Arg and was classified Pathogenic in ClinVar (VCV000003491.3). ClinVar accession VCV000419332.13 classifies WT1 p.Arg467Gln as Likely Pathogenic/Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;.;.;.;.;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;.;.;.
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D;.;.;.
Sift4G	Uncertain	0.0080	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.92
MVP		0.87
ClinPred		1.0	D
GERP RS		6.0
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-32413565; COSMIC: COSV60069955; COSMIC: COSV60069955;