rs142059681

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM5BP6BS2

The NM_024426.6(WT1):c.1063T>C(p.Cys355Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C355G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 0 hom. )

Consequence

WT1
NM_024426.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: 3.45

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 (HGNC:):

WT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a zinc_finger_region C2H2-type 2 (size 24) in uniprot entity WT1_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_024426.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP6

Variant 11-32399998-A-G is Benign according to our data. Variant chr11-32399998-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41847.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=1}. Variant chr11-32399998-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6 linkuse as main transcript	c.1063T>C	p.Cys355Arg	missense_variant	6/10	ENST00000452863.10	NP_077744.4	P19544-7Q6PI38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10 linkuse as main transcript	c.1063T>C	p.Cys355Arg	missense_variant	6/10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000533

AC:

134

AN:

251462

Hom.:

AF XY:

0.000552

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000791

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000819

AC:

1198

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000829

AC XY:

603

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000986

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.000401

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000748

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer as well as in males with oligozoospermia (PMID: 35264596, 30306255, 25451826); This variant is associated with the following publications: (PMID: 30219896, 24728327, 29399405, 25451826, 28780565, 30306255, 25645356, 34518484, 22703879, 35264596) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

WT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 25, 2020

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

.;.;.;.;.;.;.;.;D

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;.;T;.;.;.;.;.;.

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.61

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.34

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.0

D;D;D;D;D;.;.;.;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.023

D;D;D;D;D;.;.;.;D

Sift4G

Uncertain

0.022

D;D;D;D;D;.;.;.;D

Polyphen

0.98

D;.;.;.;.;.;.;.;.

Vest4

0.79

MVP

0.85

ClinPred

0.077

GERP RS

6.0

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over