11-32388003-A-AACAC

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.*1051_*1054dupGTGT 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 0.0097 ( 12 hom., cov: 0)

Exomes 𝑓: 0.0086 ( 0 hom. )

Consequence

WT1
NM_024426.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:4

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 nfe. GnomAd4 allele frequency = 0.00967 (1417/146578) while in subpopulation NFE AF = 0.0134 (883/65912). AF 95% confidence interval is 0.0127. There are 12 homozygotes in GnomAd4. There are 657 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 1417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6 link	c.1051_1054dupGTGT		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.1051_1054dupGTGT		3_prime_UTR_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5		P19544-7A0A0A0MT54

Frequencies

GnomAD3 genomes

AF:

0.00967

AC:

1416

AN:

146462

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00257

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.00737

Gnomad EAS

AF:

0.00100

Gnomad SAS

AF:

0.00482

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.0134

GnomAD4 exome

AF:

0.00864

AC:

713

AN:

82480

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

310

AN XY:

38080

show subpopulations

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

African (AFR)

AF:

0.00257

AC:

AN:

3892

American (AMR)

AF:

0.0120

AC:

AN:

2502

Ashkenazi Jewish (ASJ)

AF:

0.00645

AC:

AN:

5114

East Asian (EAS)

AF:

0.00601

AC:

AN:

11486

South Asian (SAS)

AF:

0.00575

AC:

AN:

696

European-Finnish (FIN)

AF:

0.0213

AC:

AN:

750

Middle Eastern (MID)

AF:

0.00813

AC:

AN:

492

European-Non Finnish (NFE)

AF:

0.00973

AC:

494

AN:

50750

Other (OTH)

AF:

0.00780

AC:

AN:

6798

⚠️ 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: 0.294

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00967

AC:

1417

AN:

146578

Hom.:

Cov.:

AF XY:

0.00922

AC XY:

657

AN XY:

71292

show subpopulations

African (AFR)

AF:

0.00258

AC:

104

AN:

40234

American (AMR)

AF:

0.0112

AC:

165

AN:

14718

Ashkenazi Jewish (ASJ)

AF:

0.00737

AC:

AN:

3390

East Asian (EAS)

AF:

0.00101

AC:

AN:

4972

South Asian (SAS)

AF:

0.00482

AC:

AN:

4562

European-Finnish (FIN)

AF:

0.0194

AC:

186

AN:

9588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0134

AC:

883

AN:

65912

Other (OTH)

AF:

0.0133

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0232

Hom.:

Bravo

AF:

0.00818

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nephroblastoma

Uncertain:1

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:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meacham syndrome

Uncertain:1

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:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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11-32388003-A-AACAC

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