Genetic Variant WT1:c.1447+5G>A (chr11-32391967-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_024426.6(WT1):c.1447+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WT1
NM_024426.6 splice_region, intron

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 7.87

Publications

10 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Frasier syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-32391967-C-T is Pathogenic according to our data. Variant chr11-32391967-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024426.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WT1	NM_024426.6	MANE Select	c.1447+5G>A	splice_region intron	N/A	NP_077744.4
WT1	NM_024424.5		c.1438+14G>A	intron	N/A	NP_077742.3	H0Y7K5
WT1	NM_001407044.1		c.1432+14G>A	intron	N/A	NP_001393973.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WT1	ENST00000452863.10	TSL:1 MANE Select	c.1447+5G>A	splice_region intron	N/A	ENSP00000415516.5	P19544-7
WT1	ENST00000639563.4	TSL:1	c.1396+5G>A	splice_region intron	N/A	ENSP00000492269.3	P19544-8
WT1	ENST00000332351.9	TSL:1	c.1387+14G>A	intron	N/A	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726750

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110984

Other (OTH)

AF:

0.00

AC:

AN:

60350

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Frasier syndrome (4)

Nephrotic syndrome, type 4 (4)

Drash syndrome (3)

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

Familial idiopathic steroid-resistant nephrotic syndrome (1)

Inborn genetic diseases (1)

Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 (1)

Wilms tumor 1 (2)

WT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

7.9

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.83

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.83

Position offset: 5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over