Genetic Variant NM_024426.6:c.121C>A (chr11-32435240-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024426.6(WT1):c.121C>A(p.Pro41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

WT1
NM_024426.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.180

Publications

0 publications found

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:

WT1-AS (HGNC:18135): (WT1 antisense RNA) This gene is located upstream of the Wilms tumor 1 (WT1) gene; these two genes are bi-directionally transcribed from the same promoter region. This gene is imprinted in kidney, with preferential expression from the paternal allele. Imprinting defects at chromosome 11p13 may contribute to tumorigenesis. [provided by RefSeq, May 2014]

WT1-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06949791).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6 link	c.121C>A	p.Pro41Thr	missense_variant	Exon 1 of 10	ENST00000452863.10	NP_077744.4	P19544-7Q6PI38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 link	c.121C>A	p.Pro41Thr	missense_variant	Exon 1 of 10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1383918

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

682924

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31614

American (AMR)

AF:

0.00

AC:

AN:

36198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25114

East Asian (EAS)

AF:

0.00

AC:

AN:

35956

South Asian (SAS)

AF:

0.00

AC:

AN:

79350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4920

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079416

Other (OTH)

AF:

0.00

AC:

AN:

57770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.41

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.069

T;T;T;T;T;T

MetaSVM

Benign

-0.98

PhyloP100

0.18

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.43

N;N;N;.;.;.

REVEL

Benign

0.022

Sift

Uncertain

0.0020

D;D;D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;.;.

Vest4

0.20

MutPred

0.22

Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);

MVP

0.099

ClinPred

0.062

GERP RS

-3.2

PromoterAI

-0.023

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over