chr11-32391968-G-A

Position:

• chr11-32391968-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_024426.6(WT1):​c.1447+4C>T variant causes a splice donor region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WT1 NM_024426.6 splice_donor_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 8.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-32391968-G-A is Pathogenic according to our data. Variant chr11-32391968-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32391968-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WT1	NM_024426.6	c.1447+4C>T		splice_donor_region_variant, intron_variant		ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1447+4C>T		splice_donor_region_variant, intron_variant		1	NM_024426.6	ENSP00000415516

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frasier syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Jan 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2018	The c.1432+4C>T variant in WT1 has been previously reported in >10 individuals with clinical features of Frasier syndrome, including in at 3 individuals with de novo occurrence (Barbaux 1997, Bastian 20115, Guaragna 2013, Hersmus 2012, Li 2010, Lispka 2013, Wang 2017) and segregated with disease in one affected family member. It was absent from large population studies and has been reported in ClinVar (Variation ID 3500). This variant is variant is located in the 5' splice region. Computational analyses and In vitro functional studies provide some evidence that the c.1432+4C>T variant may impact protein function (Barbaux 1997); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for Frasier syndrome in an autosomal dominant manner based upon de novo occurences, presence in affected individuals, absence from controls and functional evidence. ACMG/AMP Criteria applied: PM6_Strong, PP1_strong, PM2, PS3_supporting (Richards 2015). -

Nephrotic syndrome, type 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice site donor variant c.1447+4C>T in the WT1 gene has been observed in individuals with WT1-related disorders Gomes et al., 2018. Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 Buratti et al., 2007. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This splice variant in intron 9 affects the position of four nucleotides downstream of exon 9. It is submitted to ClinVar as Pathogenic multiple submissions. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 23, 2021	ACMG classification criteria: PS3 supporting, PS4, PM2, PM6, PP1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Precision Medicine Center, Zhengzhou University	Dec 01, 2023	PS2,PM2_p,PP3 -

Wilms tumor 1 Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This variant substitutes a C nucleotide with a T nucleotide in the +4 position of the intron 9 splice donor site in the WT1 gene. This variant is also known as c.1447+4C>T and IVS9+4C>T in the literature. RNA studies have found that this variant results in the increased splicing at an alternative donor site in exon 9, resulting in the deletion of the last nine nucleotides of exon 9 and the in-frame deletion of lysine (K), threonine (T) and serine (S) located in between zinc fingers 3 and 4 in the WT1 protein (PMID: 10792605, 34622098). Altered ratio between the two WT1 isoforms with and without the KTS motif are associated with Frasier syndrome (PMID: 9499425, 10561752). This variant has been reported in over 60 individuals affected with Frasier syndromes (PMID: 9398852, 9499425, 10094551, 10505699, 10670748, 10792605, 11007843, 12050205, 22908070, 25623218, 29668062, 34622098, 35211794, 36980135) and related clinical features (PMID: 9529364, 20442690, 23515051, 24161391, 30655312) and three individuals affected with Denys-Drash syndrome (PMID: 9475094). Among individuals diagnosed with Frasier syndrome at least one was affected with Wilms tumor and 19 individuals were affected with gonadal tumors (PMID: 10094551, 22908070, 25623218, 34622098). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant; typical for 46,XY 46,XY complete gonadal dysgenesis -

Nephrotic range proteinuria Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2023

This sequence change falls in intron 9 of the WT1 gene. It does not directly change the encoded amino acid sequence of the WT1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 3 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with WT1-related disorders (PMID: 9398852, 9499425, 29668062). In at least one individual the variant was observed to be de novo. This variant is also known as IVS9+4C>T. ClinVar contains an entry for this variant (Variation ID: 3500). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 (PMID: 9398852, 12050205). For these reasons, this variant has been classified as Pathogenic. -

Familial idiopathic steroid-resistant nephrotic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Nov 27, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2022

Published functional studies demonstrate a damaging effect: abnormal gene splicing (Barbaux et al., 1997); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 1658787, 9398852, 22908070, 24856380, 17934764, 27300205, 34392242, 32838737, 31937884, 30348286, 24161391, 19484379, 21508141, 23515051, 20442690, 22815844, 9529364, 25905393, 10792605, 10670748, 9475094, 12050205, 25818337, 26668027, 16439601, 16780544, 10094551, 9499425, 25813279, 28204945, 28921387, 28476686, 29869118, 29668062, 30655312, 32581362, 32887937, 32381729, 32604935) -

WT1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2023

The WT1 c.1432+4C>T variant is predicted to interfere with splicing. This variant has been well documented to be pathogenic for Frasier syndrome and steroid-resistant nephrotic syndrome with FSGS (Barbaux et al. 1997. PubMed ID: 9398852; Melo et al. 2002. PubMed ID: 12050205; Li et al. 2010. PubMed ID: 20442690; Lipska et al. 2013. PubMed ID: 23515051). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.50		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776577; hg19: chr11-32413514; COSMIC: COSV105901703; COSMIC: COSV105901703;