ZNF423
protein-codingzinc finger protein 423, the group of Zinc fingers C2H2-type
Gene summary
The protein encoded by this gene is a nuclear protein that belongs to the family of Kruppel-like C2H2 zinc finger proteins. It functions as a DNA-binding transcription factor by using distinct zinc fingers in different signaling pathways. Thus, it is thought that this gene may have multiple roles in signal transduction during development. Mutations in this gene are associated with nephronophthisis-14 and Joubert syndrome-19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~370.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009480
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013916
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013916
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011190
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: ClinGen
*ZNF423* was first reported in relation to autosomal recessive ciliopathy in 2012 (Chaki et al., PMID: 22863007). *ZNF423* has been noted to be associated with the following disease entities: Nephronophthisis 14 (NPHP14) and Joubert Syndrome 19 (JBTS19). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and phenotypic variability. Inheritance patterns show that NPHP14 is caused by biallelic variants while JBTS19 is caused by heterozygous variants in *ZNF423*. Since the significance of the JBTS patients with a single variant is not clear, this data was not scored (PMIDs: 22863007, 31216405). Therefore, the two disease entities have been lumped into one disease entity: ciliopathy (OMIM:614844). At least 11 unique variants (missense) have been reported in 7 individuals in 7 publications (PMIDs: 22863007, 26539891, 28454995, 33531950, 30076350, 31964843, 30868567). The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by biochemical function, functional alteration, protein interaction studies, and mouse models (PMID: 17151198, 17524391, 22863007, 27727273, 33517396). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on March 23, 2022. It was re-evaluated on June 26, 2024 as per SOP version 10. As a result of this reevaluation, the classification increased from Limited to Moderate with the addition of a new case-level and experimental evidence (PMIDs: 26539891, 28454995, 27727273, 30868567).
Inheritance Pattern: AR
Disease ID:MONDO:0013916
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013916
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013916
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0013916
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Clinical Genomic Database (CGD)
Manifestation: Neurologic; Ophthalmologic; Pulmonary; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: The conditions can involve manifestations including renal disease and anomalous perinatal breathing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ZNF423 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001379286.1. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 365 | 11 | 379 | ||
| missense | 1 | 3 | 471 | 15 | 1 | 491 |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 1 | 2 | 5 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 4 | 479 | 380 | 12 | 878 |
Highest pathogenic variant AF is 0.00001672765
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001366215.1 | 8 | MANE Select | |
| Ensembl | ENSP00000455588.3 | 8 | MANE Select | |
| RefSeq | NP_001258549.1 | 6 | Standard | |
| RefSeq | NP_001317462.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- White fat cell differentiation
- Differentiation of white and brown adipocyte
- White fat cell differentiation
- TGF-beta Receptor Signaling
- BMP2 signaling TGF-beta MV
Biological Process
- regulation of transcription, DNA-templated
- Notch signaling pathway
- nervous system development
- cell differentiation
- positive regulation of BMP signaling pathway
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
- protein binding
- metal ion binding
Cellular Component
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000561648
- Coding exons
- 8
- Length
- 370396
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125748
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.49 | 625 | 826 | 0.756 | 0.0000540 | 8635 |
| Missense (PolyPhen) | 157 | 300.51 | 0.52244 | 3252 | ||
| Synonymous | -1.12 | 395 | 368 | 1.07 | 0.0000281 | 2366 |
| Loss of Function | 5.54 | 3 | 41.6 | 0.0722 | 0.00000178 | 516 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that can both act as an activator or a repressor depending on the context. Plays a central role in BMP signaling and olfactory neurogenesis. Associates with SMADs in response to BMP2 leading to activate transcription of BMP target genes. Acts as a transcriptional repressor via its interaction with EBF1, a transcription factor involved in terminal olfactory receptor neurons differentiation; this interaction preventing EBF1 to bind DNA and activate olfactory-specific genes. Involved in olfactory neurogenesis by participating in a developmental switch that regulates the transition from differentiation to maturation in olfactory receptor neurons. Controls proliferation and differentiation of neural precursors in cerebellar vermis formation. {ECO:0000269|PubMed:10660046}.;
- Disease
- DISEASE: Nephronophthisis 14 (NPHP14) [MIM:614844]: An autosomal recessive disorder manifesting as infantile-onset kidney disease, cerebellar vermis hypoplasia, and situs inversus. Nephronophthisis is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. {ECO:0000269|PubMed:22863007}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 19 (JBTS19) [MIM:614844]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). JBTS19 patients have polycystic kidney disease, Leber congenital amaurosis, cerebellar vermis hypoplasia, and breathing abnormality. {ECO:0000269|PubMed:22863007}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.122
Intolerance Scores
- LoFtool
- 0.0347
- RVIS EVS
- -2.2
- RVIS percentile EVS
- 1.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.760
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |