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NM_024426.6(WT1):c.1447+5G>A AND Nephrotic syndrome, type 4

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Mar 14, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000589623.9

Allele description [Variation Report for NM_024426.6(WT1):c.1447+5G>A]

NM_024426.6(WT1):c.1447+5G>A

Gene:
WT1:WT1 transcription factor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p13
Genomic location:
Preferred name:
NM_024426.6(WT1):c.1447+5G>A
Other names:
splice site; 1432+5G>A; IVS9+5G>A
HGVS:
  • NC_000011.10:g.32391967C>T
  • NG_009272.1:g.48575G>A
  • NM_000378.6:c.1387+14G>A
  • NM_001198551.2:c.787+14G>A
  • NM_001198552.2:c.745+5G>A
  • NM_001367854.1:c.259+5G>A
  • NM_001407044.1:c.1432+14G>A
  • NM_001407045.1:c.1396+5G>A
  • NM_001407046.1:c.1354+699G>A
  • NM_001407047.1:c.1315+14G>A
  • NM_001407048.1:c.1306+5G>A
  • NM_001407049.1:c.1303+699G>A
  • NM_001407050.1:c.1273+5G>A
  • NM_001407051.1:c.685+5G>A
  • NM_024424.5:c.1438+14G>A
  • NM_024426.6:c.1447+5G>AMANE SELECT
  • LRG_525:g.48575G>A
  • NC_000011.9:g.32413513C>T
  • NM_024426.2:c.1228+5G>A
  • NM_024426.4:c.1432+5G>A
Nucleotide change:
IVS9DS, G-A, +5
Links:
OMIM: 607102.0009; OMIM: 607102.0020; dbSNP: rs587776576
NCBI 1000 Genomes Browser:
rs587776576
Molecular consequence:
  • NM_000378.6:c.1387+14G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001198551.2:c.787+14G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001198552.2:c.745+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001367854.1:c.259+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407044.1:c.1432+14G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407045.1:c.1396+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407046.1:c.1354+699G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407047.1:c.1315+14G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407048.1:c.1306+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407049.1:c.1303+699G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407050.1:c.1273+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001407051.1:c.685+5G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_024424.5:c.1438+14G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_024426.6:c.1447+5G>A - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Name:
Nephrotic syndrome, type 4 (NPHS4)
Synonyms:
Familial mesangial sclerosis; Nephrotic syndrome, early onset with diffuse mesangial sclerosis
Identifiers:
MONDO: MONDO:0009733; MedGen: C3151568; Orphanet: 656; OMIM: 256370

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000693892Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG)
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(May 2, 2023) 		germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

SCV000863865Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
no assertion criteria provided
Pathogenic
(May 17, 2018) 		germlineclinical testing

SCV0025729493billion
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 1, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005088811Breakthrough Genomics, Breakthrough Genomics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 14, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.

Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M.

Hum Mol Genet. 1998 Apr;7(4):709-14.

PubMed [citation]
PMID:
9499425

Genetic screening in adolescents with steroid-resistant nephrotic syndrome.

Lipska BS, Iatropoulos P, Maranta R, Caridi G, Ozaltin F, Anarat A, Balat A, Gellermann J, Trautmann A, Erdogan O, Saeed B, Emre S, Bogdanovic R, Azocar M, Balasz-Chmielewska I, Benetti E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H, et al.

Kidney Int. 2013 Jul;84(1):206-13. doi: 10.1038/ki.2013.93. Epub 2013 Mar 20.

PubMed [citation]
PMID:
23515051
See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG), SCV000693892.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The heterozygous c.1432+5G>A variant in WT1 was identified by our study in one individual with steroid-resistant nephrotic syndrome. Trio exome analysis revealed this variant to be de novo. The c.1432+5G>A variant in WT1 has been reported in 19 unrelated individuals with WT1 disorder (PMID: 23295293, PMID: 27719739, PMID: 21499692, PMID: 22099579, PMID: 24856380, PMID: 10762296, PMID: 20442690, PMID: 9499425, PMID: 1302008). This variant was found to be de novo in 13 individuals with confirmed paternity and maternity (PMID: 28204945, PMID: 28780565, PMID: 23515051, PMID: 21499692, PMID: 17694336, PMID: 10762296, PMID: 9499425, PMID: 1302008). This variant is assumed de novo in 10 individuals, but maternity and paternity have not been confirmed (PMID: 23295293, PMID: 27719739, PMID: 28204945, PMID: 22099579, PMID: 24856380, PMID: 9499425). This variant has also been reported in ClinVar (Variation ID: 3493) and has been interpreted as pathogenic by multiple submitters. Multiple variants in the same region as the c.1432+5G>A variant have been reported in association with disease, suggesting that this variant is in a hot spot and slightly supports pathogenicity (PMID: 9499425). This variant was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. RT-PCR analysis performed on affected tissue shows this variant results in altered splicing of WT1, leading to an altered ratio of the +/- KTS isoforms (PMID: 17694336, PMID: 9499425, PMID: 1302008). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant WT1 disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3_Moderate, PS4, PM1_Supporting, PM2_Supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, SCV000863865.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From 3billion, SCV002572949.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.83). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 23515051). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003493 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Breakthrough Genomics, Breakthrough Genomics, SCV005088811.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant lies in the splice donor site, in intron 9 of the WT1 gene. In silico splice prediction tools (ASSP and NNSPLICE) predicted this variant to interfere with splicing. The variant (also known as 1228+5G>A and IVS9+5G>A) has been reported in the in multiple individuals with Frasier syndrome and/or early-onset nephrotic syndrome [PMID: 23515051, 1302008, 20442690]. In vitro functional studies indicate that this variant results in defective splicing resulting in disruption of the ratio of WT1 isoforms [PMID: 9499425].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024