ZMYND10
protein-codingzinc finger MYND-type containing 10, the group of Axonemal dynein assembly factors|Zinc fingers MYND-type
Gene summary
This gene encodes a protein containing a MYND-type zinc finger domain that likely functions in assembly of the dynein motor. Mutations in this gene can cause primary ciliary dyskinesia. This gene is also considered a tumor suppressor gene and is often mutated, deleted, or hypermethylated and silenced in cancer cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014192
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014192
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014192
Submitter: ClinGen
The *ZMYND10* gene was first reported in relation to primary ciliary dyskinesia in 2013 (Zariwala et al., PMID: 23891469, Moore et al., PMID: 23891471). The specific disease entity, primary ciliary dyskinesia 22 (MONDO:0014192, OMIM #615444), is one of at least 45 different primary ciliary dyskinesias (PCD) distinguished by a single monogenic cause. Affected patients can have onset of symptoms at birth and reported cases have been diagnosed with PCD either in infancy or in childhood. Frequent features among reported patients are chronic wet cough from early childhood, neonatal respiratory distress, sinusitis, otitis media, bronchiectasis, and decreased nasal nitric oxide. Approximately 50% of cases exhibit situs inversus or heterotaxy. Cilia are largely or completely immotile. Adult patients can exhibit decreased fertility. Biopsies of the airway epithelium show ciliary ultrastructure with absent or abnormal outer and inner dynein arms, although one reported case with a PCD-associated phenotype and homozygous missense variant has been found to exhibit normal ciliary ultrastructure (PMID: 23891469, and personal communication with the authors). This finding emphasizes the clear need for additional case reports to establish the full extent of outer and inner dynein arm defects in *ZMYND10*-related disease. This curation has scored eleven suspected deleterious *ZMYND10* variants (two missense, six frameshift, and three nonsense), which were collectively reported in twelve probands in three publications (PMID: 23891471, PMID: 23891469, PMID: 26139845). All of the probands harbored biallelic variants confirmed to be present in trans. Nine probands harbored variants in the homozygous state, four of whom were reported to be from consanguineous parents. Three others probands harbored *ZMYND10* variants in the compound heterozygous state. The molecular mechanism appears to be biallelic loss-of-function with an autosomal recessive mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product. More genetic evidence was available (PMID: 26824761) but was not included as the maximum for this category of evidence had already been reached. Large families with segregation data were not found for inclusion in this gene curation. Please note that the genetic evidence scored in this curation has relied heavily on the best-characterized *ZMYND10* variants from the literature, while an urgent need remains for additional published data to evaluate the pathogenicity of many other emerging variants. This gene-disease relationship is also supported by experimental evidence that high levels of *ZMYND10* expression in humans (PMID: 23715323) and mice (PMID: 23891471) are specific to tissues known to harbor multi-ciliated cells. *ZMYND10* expression also increases dramatically when cultured human bronchial epithelial cells are subjected to conditions that stimulate ciliogenesis (PMID: 17413031). Biochemical studies indicate that the ZMYND10 protein interacts with the chaperone molecules FKBP8 and HSP90, functioning as a required chaperone during cytoplasmic pre-assembly of dyneins (PMID: 29916806). Animal models lacking Zmynd10 exhibit destabilization of dynein arm components (PMID: 29916806). ZMYND10 also physically interacts with the protein product of the LRRC6 / DNAAF11 gene, which harbors variants known to cause another form of PCD (PMID: 23891471). *Drosophila*, zebrafish, and medaka models with biallelic silencing or deletion of the respective genes orthologous to *ZMYND10* recapitulate cellular and organ-level features of the human disease state (PMID: 23891469, PMID: 23891471, PMID: 28823919). Mouse models in particular exhibit absent outer and inner dynein arms, situs inversus totalis, mucopurulent nasal plugs, and reduced motility of cilia and sperm (PMID: 29916806). Rescue experiments have demonstrated the potential of a wild-type transgene from *Drosophila*, medaka, or mouse to rescue phenotypes of endogenous *Zmynd10* disruption in various model organisms (PMID: 28823919, PMID: 23891471). In summary, *ZMYND10* is definitively associated with primary ciliary dyskinesia 22. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Motile Ciliopathy GCEP on February 7th, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0016575
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014192
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014192
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Pulmonary
Rationale: Pulmonary and audiologic surveillance may be beneficial to assess respiratory and hearing function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial, though measures including lobectomy or lung transplantation may be necessary; The condition can involve congenital cardiac anomalies, and awareness may allow early management
Comments: The condition can involve multiple anomalies, and individuals may require surgery or other interventions related to findings such as congenital cardiac malformations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ZMYND10 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015896.4. 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 | 4 | 60 | 64 | |||
| missense | 3 | 2 | 118 | 14 | 137 | |
| nonsense | 8 | 4 | 1 | 13 | ||
| start loss | 2 | 2 | ||||
| frameshift | 7 | 5 | 1 | 13 | ||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 1 | 8 | ||
| Total | 21 | 17 | 125 | 74 | 0 | 237 |
Highest pathogenic variant AF is 0.0002565552
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_056980.2 | 12 | MANE Select | |
| Ensembl | ENSP00000231749.3 | 12 | MANE Select | |
| RefSeq | NP_001295308.1 | 11 | Standard | |
| Ensembl | ENSP00000353289.3 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| zmynd10 | Danio rerio | Structure: otolith Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- outer dynein arm assembly
- inner dynein arm assembly
- motile cilium assembly
- positive regulation of motile cilium assembly
Molecular Function
- protein binding
- metal ion binding
Cellular Component
- cytoplasm
- apical plasma membrane
- centriolar satellite
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000231749
- Coding exons
- 12
- Length
- 5743
- Individuals with no LoFs
- 125706
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125748
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.932 | 208 | 249 | 0.834 | 0.0000137 | 2841 |
| Missense (PolyPhen) | 39 | 51.692 | 0.75447 | 599 | ||
| Synonymous | 1.58 | 82 | 102 | 0.802 | 0.00000518 | 867 |
| Loss of Function | 2.12 | 15 | 26.9 | 0.558 | 0.00000133 | 289 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00018 | 0.00018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in axonemal structure organization and motility (PubMed:23891469, PubMed:23891471). Involved in axonemal pre-assembly of inner and outer dynein arms (IDA and ODA, respectively) for proper axoneme building for cilia motility (By similarity). May act by indirectly regulating transcription of dynein proteins (By similarity). {ECO:0000250|UniProtKB:Q99ML0, ECO:0000269|PubMed:23891469, ECO:0000269|PubMed:23891471}.;
- Disease
- DISEASE: Ciliary dyskinesia, primary, 22 (CILD22) [MIM:615444]: A disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. Patients may exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. {ECO:0000269|PubMed:23891469, ECO:0000269|PubMed:23891471, ECO:0000269|PubMed:25186273, ECO:0000269|PubMed:29601588}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.226
Intolerance Scores
- LoFtool
- 0.443
- RVIS EVS
- 0.37
- RVIS percentile EVS
- 75.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.721
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |