11-32388003-AACACACACACACACACACAC-AACACACACACACACACACACAC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_024426.6(WT1):c.*1053_*1054dupGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.040 ( 119 hom., cov: 0)

Exomes 𝑓: 0.037 ( 0 hom. )

Consequence

WT1
NM_024426.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 1.29

Publications

2 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 Gene-Disease associations (from GenCC):

Denys-Drash syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
Wilms tumor 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Frasier syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0398 (5828/146512) while in subpopulation AMR AF = 0.0513 (754/14702). AF 95% confidence interval is 0.0483. There are 119 homozygotes in GnomAd4. There are 2694 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6 link	c.1053_1054dupGT		3_prime_UTR_variant	Exon 10 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.1053_1054dupGT		3_prime_UTR_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

AF:

0.0397

AC:

5819

AN:

146396

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0389

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.0513

Gnomad ASJ

AF:

0.0209

Gnomad EAS

AF:

0.0241

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.0288

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0499

GnomAD4 exome

AF:

0.0371

AC:

3052

AN:

82374

Hom.:

Cov.:

AF XY:

0.0370

AC XY:

1406

AN XY:

38014

show subpopulations

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

African (AFR)

AF:

0.0376

AC:

146

AN:

3884

American (AMR)

AF:

0.0443

AC:

111

AN:

2504

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

AN:

5110

East Asian (EAS)

AF:

0.0483

AC:

554

AN:

11474

South Asian (SAS)

AF:

0.0101

AC:

AN:

696

European-Finnish (FIN)

AF:

0.0173

AC:

AN:

750

Middle Eastern (MID)

AF:

0.0328

AC:

AN:

488

European-Non Finnish (NFE)

AF:

0.0373

AC:

1892

AN:

50680

Other (OTH)

AF:

0.0349

AC:

237

AN:

6788

⚠️ 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: 0.327

Heterozygous variant carriers

203

405

608

810

1013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0398

AC:

5828

AN:

146512

Hom.:

119

Cov.:

AF XY:

0.0378

AC XY:

2694

AN XY:

71250

show subpopulations

African (AFR)

AF:

0.0390

AC:

1569

AN:

40212

American (AMR)

AF:

0.0513

AC:

754

AN:

14702

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

AN:

3390

East Asian (EAS)

AF:

0.0243

AC:

121

AN:

4972

South Asian (SAS)

AF:

0.0191

AC:

AN:

4560

European-Finnish (FIN)

AF:

0.0213

AC:

204

AN:

9572

Middle Eastern (MID)

AF:

0.0278

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0426

AC:

2808

AN:

65904

Other (OTH)

AF:

0.0493

AC:

100

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

254

509

763

1018

1272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0190

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephroblastoma

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

11p partial monosomy syndrome

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meacham syndrome

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephrotic syndrome, type 4

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-32388003-AACACACACACACACACACAC-AACACACACACACACACACACAC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over