11-32400025-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_024426.6(WT1):c.1036A>G(p.Ser346Gly) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S346R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.28

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a zinc_finger_region C2H2-type 1 (size 24) in uniprot entity WT1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_024426.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-32400025-T-C is Pathogenic according to our data. Variant chr11-32400025-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3499.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.1036A>G	p.Ser346Gly	missense_variant	6/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10	c.1036A>G	p.Ser346Gly	missense_variant	6/10	1	NM_024426.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mesothelioma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.0062
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;.;D;.;.;.;.;.;.
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N;N;N;N;N;.;.;.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D;D;D;D;.;.;.;D
Sift4G	Benign	0.15	T;T;T;T;T;.;.;.;D
Polyphen		0.15	B;.;.;.;.;.;.;.;.
Vest4		0.37
MVP		0.83
ClinPred		0.92	D
GERP RS		6.0
gMVP		0.41

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

Other links and lift over

dbSNP: rs121907908; hg19: chr11-32421571; COSMIC: COSV60080661;