NOP10
protein-codingNOP10 ribonucleoprotein, the group of H/ACA ribonucleoprotein complex
Gene summary
This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA processing and modification and have been classified into two families: C/D and H/ACA. The H/ACA snoRNPs also include the DKC1, NOLA1 and NOLA2 proteins. These four H/ACA snoRNP proteins localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. The four H/ACA snoRNP proteins are also components of the telomerase complex. This gene encodes a protein related to Saccharomyces cerevisiae Nop10p. [provided by RefSeq, Jul 2008]
- NOLA3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0015780
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0957294
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0957294
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009136
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0957294
Submitter: ClinGen
*NOP10* was first reported in relation to semidominant pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9 in 2020 (Kannengiesser C et al., PMID:32139460). Some patients present with pulmonary fibrosis, in the heterozygous state typically later in life; some patients present with extrapulmonary phenotype earlier in life. Individuals with dyskeratosis congenita are also included in this curation. Dyskeratosis congenita is a multisystem disorder that variably includes nail, skin and mucosal findings, bone marrow failure, cancer predisposition, interstitial lung disease and hepatic fibrosis, among other manifestations. In the index family reported by Kannengiesser C et al., two individuals are deceased from leukemia (death age 26 and 61) and one individual had long term leukopenia (age 43 at report). These findings are relevant to the possible association between *NOP10* and childhood, adolescent and young adult cancer predisposition. At least 2 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in *NOP10* have been reported in individuals with the following disease entities: Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 2; Dyskeratosis congenita, autosomal recessive 1; and Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or phenotypic variability between the pulmonary fibrosis and dyskeratosis congenita phenotypes. Therefore, those entities have been lumped into one disease entity (OMIM:620400) and split from the cataracts phenotype. This gene-disease relationship is supported by a cell model showing that the knockdown of *NOP10* using siRNAs results in reduced TERC expression, which is consistent with patient cell assays (PMID:17507419) and coimmunoprecipitation that shows the physical association of *NOP10* protein with DKC1 protein, DKC1 has been implicated in the same disease by this expert panel (PMID:11074001). Variants in this gene have been reported in at least 2 probands in 2 publications (PMID:32139460, 17507419). Variants in this gene segregated with disease in five additional family members with more having been tested. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Interstitial Lung Disease Gene Curation Expert Panel on the meeting date 18 March 2025 (SOP Version 11). The Childhood, Adolescent and Young Adult Cancer Predisposition GCEP participated in discussion and contributed to our classification of this gene as a secondary contributor.
Inheritance Pattern: AR
Disease ID:MONDO:0009136
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009136
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009136
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0100137
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dental; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Neurologic; Oncologic; Pulmonary; Renal
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Gastrointestinal; Hematologic; Oncologic; Pulmonary; Renal
Rationale: Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related can involve hepatic manifestations, and awareness may allow early diagnosis and medical and surgical management; Surveillance and prompt treatment of findings related to hematologic sequelae (including risk of malignancy) may be beneficial; For treatment related to pulmonary fibrosis, early recognition may allow prompt medical management; In Dyskeratosis congenita, autosomal recessive 1, surveillance (eg, with regularly performed CBC as well as other measures in the presence of concern for hematologic sequelae) for bone marrow failure, as well as surveillance for multiple cancer types (eg, with self-examination and clinical examination), and pulmonary disease may allow early detection and treatment; Lung transplant may be indicated in individuals with advanced lung diease; HSCT may be indicated due to manifestations including leukemia and bone marrow failure (which may also be treated with androgen therapy), but the long-term efficacy may not be optimal; Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 2 can involve early-onset hearing loss and renal disease, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Identification and management of renal sequelae may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NOP10 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018648.4. 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 | 12 | 12 | ||||
| missense | 1 | 31 | 1 | 33 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 1 | 0 | 38 | 12 | 1 | 52 |
Highest pathogenic variant AF is 6.8414147e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_061118.1 | 2 | MANE Select | |
| Ensembl | ENSP00000332198.5 | 2 | MANE Select | |
| Ensembl | ENSP00000453475.1 | 2 | Standard | |
| Ensembl | ENSP00000453475.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nop10 | Danio rerio | Structure: nucleate erythrocyte Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ribosome biogenesis in eukaryotes - Homo sapiens (human)
- rRNA processing
- Metabolism of RNA
- rRNA modification in the nucleus and cytosol
- rRNA processing in the nucleus and cytosol
Biological Process
- snoRNA guided rRNA pseudouridine synthesis
- pseudouridine synthesis
- telomere maintenance via telomerase
- rRNA pseudouridine synthesis
- snRNA pseudouridine synthesis
Molecular Function
- RNA binding
- protein binding
- box H/ACA snoRNA binding
- telomerase RNA binding
Cellular Component
- nucleoplasm
- telomerase holoenzyme complex
- small nucleolar ribonucleoprotein complex
- nuclear body
- box H/ACA snoRNP complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000328848
- Coding exons
- 2
- Length
- 1462
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125735
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.317 | 33 | 38.5 | 0.856 | 0.00000258 | 409 |
| Missense (PolyPhen) | 8 | 9.8308 | 0.81377 | 137 | ||
| Synonymous | 0.969 | 10 | 14.7 | 0.679 | 8.12e-7 | 126 |
| Loss of Function | 2.04 | 0 | 4.86 | 0.00 | 3.63e-7 | 37 |
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: Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ("psi") residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme. {ECO:0000269|PubMed:15044956}.;
- Disease
- DISEASE: Dyskeratosis congenita, autosomal recessive, 1 (DKCB1) [MIM:224230]: A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. {ECO:0000269|PubMed:17507419}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.343
- RVIS EVS
- 0.3
- RVIS percentile EVS
- 71.81
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.955
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |