PARN
protein-codingpoly(A)-specific ribonuclease, the group of PARN exonuclease family|Ribosomal biogenesis factors
Gene summary
The protein encoded by this gene is a 3'-exoribonuclease, with similarity to the RNase D family of 3'-exonucleases. It prefers poly(A) as the substrate, hence, efficiently degrades poly(A) tails of mRNAs. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. This protein is also involved in silencing of certain maternal mRNAs during oocyte maturation and early embryonic development, as well as in nonsense-mediated decay (NMD) of mRNAs that contain premature stop codons. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~197.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: SD
Disease ID:MONDO:0014612
Submitter: ClinGen
*PARN* was first reported in relation to semidominant *PARN*-related short telomere syndrome in 2015 (Stuart BD, et al., PMID: 25848748). The features of *PARN*-related short telomere syndrome are variable, but can include oral leukoplakia, nail dystrophy, abnormal skin pigmentation, premature graying of the hair, cerebellar hypoplasia, bone marrow failure, pulmonary fibrosis, and short telomere length (PMIDs: 25893599, 25848748). Pulmonary phenotypes have been seen both in isolation and as part of a syndromic presentation (PMID: 34479523). In addition to a variable phenotype, there is also incomplete penetrance of pulmonary fibrosis in individuals who have monoallelic *PARN* variants (PMID: 25848748). Typically, pediatric presentation is often in the context of the Hoyerall-Hreidarsson syndrome or dyskeratosis congenita, whereas pulmonary fibrosis is the most common manifestation in adulthood. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: dyskeratosis congenita, autosomal recessive 6 (OMIM: 616353), pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4 (OMIM: 616371), Hoyeraal-Hreidarsson syndrome (ORPHA:3322). Thirteen variants (4 missense, 3 frameshift, 3 canonical splice-site, 2 nonsense, 1 intronic deletion) that have been reported in 11 probands across 4 publications (PMIDs: 30525901, 25893599, 25848748, 31448843) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is reported to be loss of function that results in shortened telomeres. This gene-disease relationship is also supported by experimental evidence including biochemical function data showing a shared function with other genes that cause short telomere syndromes (PMIDs: 26482878, 20301779, 20301408). In addition, functional alteration assays in non-patient cells exhibiting reduced deadenylation of telomerase RNA and subsequent decrease in telomerase activity (PMIDs: 31273937, 25893599), a cell culture model showing reduced *PARN* protein level and shortened telomeres (PMID: 31448843), and a knockdown zebrafish model system that has a hematological phenotype similar to the human bone marrow phenotype, which is rescued by injection of human *PARN* mRNA (PMID: 26342108). In summary, there is definitive evidence supporting the relationship between *PARN* and semidominant *PARN*-related short telomere syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date October 25, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0014600
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014600
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015780
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018045
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014600
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014612
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014612
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0014612
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Hematologic; Neurologic; Oncologic; Pulmonary
Intervention: Hematologic; Oncologic; Pulmonary
Rationale: In dyskeratosis congenita, the presentation many not always be classic, and individuals are at high risk for hematologic anomalies (including bone marrow failure) and malignancy, and surveillance and prompt diagnosis and treatment may be beneficial; In Aplastic anemia, surveillance and prompt treatment of aplastic anemia and bone marrow failure may reduce morbidity; For treatment related to pulmonary fibrosis, immunotherapy may be beneficial, though lung transplantation may be indicated in individuals with severe/refractory disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PARN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002582.4. 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 | 9 | 150 | 159 | |||
| missense | 6 | 409 | 10 | 1 | 426 | |
| nonsense | 17 | 5 | 1 | 23 | ||
| start loss | 0 | |||||
| frameshift | 22 | 12 | 2 | 36 | ||
| splice donor/acceptor (+/-2bp) | 2 | 32 | 12 | 46 | ||
| Total | 41 | 55 | 433 | 160 | 1 | 690 |
Highest pathogenic variant AF is 0.00006556732
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002573.1 | 24 | MANE Select | |
| Ensembl | ENSP00000387911.2 | 24 | MANE Select | |
| RefSeq | NP_001127949.1 | 21 | Standard | |
| RefSeq | NP_001229921.1 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| parn | Danio rerio | Structure: myeloid cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA degradation - Homo sapiens (human)
- Lung fibrosis
- KSRP (KHSRP) binds and destabilizes mRNA
- Metabolism of RNA
- Regulation of mRNA stability by proteins that bind AU-rich elements
Biological Process
- nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
- nuclear-transcribed mRNA poly(A) tail shortening
- box H/ACA snoRNA 3'-end processing
- female gamete generation
- RNA modification
Molecular Function
- 3'-5'-exoribonuclease activity
- RNA binding
- mRNA 3'-UTR binding
- nuclease activity
- poly(A)-specific ribonuclease activity
Cellular Component
- nucleus
- nucleolus
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000437198
- Coding exons
- 24
- Length
- 197028
- Individuals with no LoFs
- 124614
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 124636
- p
- 0.0000883
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.794 | 285 | 325 | 0.876 | 0.0000166 | 4218 |
| Missense (PolyPhen) | 62 | 91.965 | 0.67417 | 1206 | ||
| Synonymous | 0.573 | 108 | 116 | 0.932 | 0.00000645 | 1066 |
| Loss of Function | 4.02 | 14 | 42.2 | 0.332 | 0.00000193 | 569 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00014 | 0.00013 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000091 | 0.000088 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: 3'-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs and is also used to silence certain maternal mRNAs translationally during oocyte maturation and early embryonic development. Interacts with both the 3'-end poly(A) tail and the 5'-end cap structure during degradation, the interaction with the cap structure being required for an efficient degradation of poly(A) tails. Involved in nonsense-mediated mRNA decay, a critical process of selective degradation of mRNAs that contain premature stop codons. Also involved in degradation of inherently unstable mRNAs that contain AU-rich elements (AREs) in their 3'-UTR, possibly via its interaction with KHSRP. Probably mediates the removal of poly(A) tails of AREs mRNAs, which constitutes the first step of destabilization (PubMed:10882133, PubMed:11359775, PubMed:12748283, PubMed:15175153, PubMed:9736620). Also able to recognize and trim poly(A) tails of microRNAs such as MIR21 and H/ACA box snoRNAs (small nucleolar RNAs) leading to microRNAs degradation or snoRNA increased stability (PubMed:25049417, PubMed:22442037). {ECO:0000269|PubMed:10882133, ECO:0000269|PubMed:11359775, ECO:0000269|PubMed:12748283, ECO:0000269|PubMed:15175153, ECO:0000269|PubMed:22442037, ECO:0000269|PubMed:25049417, ECO:0000269|PubMed:9736620}.;
- Disease
- DISEASE: Dyskeratosis congenita, autosomal recessive, 6 (DKCB6) [MIM:616353]: A form of dyskeratosis congenita, 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:25893599}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pulmonary fibrosis, and/or bone marrow failure, telomere- related, 4 (PFBMFT4) [MIM:616371]: A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. {ECO:0000269|PubMed:25848748}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- RVIS EVS
- -0.56
- RVIS percentile EVS
- 19.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.966
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |