TINF2
protein-codingTERF1 interacting nuclear factor 2, the group of Shelterin complex
Gene summary
This gene encodes one of the proteins of the shelterin, or telosome, complex which protects telomeres by allowing the cell to distinguish between telomeres and regions of DNA damage. The protein encoded by this gene is a critical part of shelterin; it interacts with the three DNA-binding proteins of the shelterin complex, and it is important for assembly of the complex. Mutations in this gene cause dyskeratosis congenita (DKC), an inherited bone marrow failure syndrome. [provided by RefSeq, Mar 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013522
Submitter: ClinGen
*TINF2* was first reported in relation to dyskeratosis congenita, autosomal dominant 3 (MONDO: 0013522) in 2008 (Savage et al., 2008 PMID: 18252230). It is caused by mutations in the *TINF2* gene, which encodes a component of shelterin, a six-protein complex that coats the telomere and is essential for suppressing the DNA damage response at telomeres (Kirwan et al., 2009; PMID:19419704). This disorder is related to telomere biology disorders (DC/TBD) which are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic Dyskeratosis congenita (DC) as well as those with a clinical picture that is dominated by dysfunction of a single organ, such as pulmonary fibrosis. Two forms of DC/TBD with more severe manifestations have been identified, Hoyeraal Hreidarsson syndrome, and Revesz syndrome, which were previously thought to be distinct disorders, but are now recognized to be part of the phenotypic spectrum of DC (Savage SA et al., 2023. Dyskeratosis Congenita and Related Telomere Biology Disorders. GeneReviews). While pulmonary fibrosis is part of the phenotypic spectrum of DC, cases of isolated fibrotic interstitial lung disease have been observed without other characteristic features of DC. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions suggesting that these may constitute a disease spectrum associated with variants in *TINF2*. Therefore, the four conditions– dyskeratosis congenita, autosomal dominant 3 (OMIM:613990), Revesz syndrome (OMIM:268130), Hoyeraal-Hreidarsson syndrome (ORPHA:3322), and pulmonary fibrosis (OMIM:178500), have been lumped into one disease entity– *TINF2*-related short telomere syndrome. Eight variants that have been reported in 12 probands in 7 publications (Tsangaris E, et al., 2008, PMID:18979121; Sasa GS, et al., 2012, PMID:21477109; Savage SA, et al., 2008, PMID:18252230; v Walne AJ, et al., 2008, PMID:18669893; Touzot F, et al., 2012, PMID:22078571; Geng J, et al., 2022, PMID:36073719; Vulliamy T, et al., 2012, PMID:21199492), are included in this curation. This gene-disease relationship is also supported by protein interactions, functional alteration studies, a cell-culture model, a mouse model (Liu D, et al., 2004, PMID:15181449; Touzot F, et al., 2012, PMID:22078571; Yang D, et al., 2011, PMID:21536674; Choo S et al., 2022, PMID:35421215; Frescas D et al., 2014, PMID:24449270; Frank AK et al., 2015, PMID:26230315 ). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. In summary, there is definitive evidence to support the relationship between *TINF2* and *TINF2*-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 November 19, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0013522
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0002771
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005075
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013522
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015780
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018045
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0009990
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0009990
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013522
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0009990
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013522
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Pulmonary
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic; Pulmonary
Rationale: 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; Awareness of infectious risk may allow prompt diagnosis and treatment of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TINF2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001099274.3. 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 | 2 | 251 | 1 | 254 | ||
| missense | 5 | 8 | 284 | 17 | 2 | 316 |
| nonsense | 3 | 4 | 6 | 13 | ||
| start loss | 1 | 1 | ||||
| frameshift | 6 | 6 | 31 | 43 | ||
| splice donor/acceptor (+/-2bp) | 1 | 11 | 12 | |||
| Total | 15 | 19 | 334 | 268 | 3 | 639 |
Highest pathogenic variant AF is 0.000087970584
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001092744.1 | 9 | MANE Select | |
| Ensembl | ENSP00000267415.7 | 9 | MANE Select | |
| RefSeq | NP_001350597.1 | 8 | Standard | |
| RefSeq | NP_036593.2 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Packaging Of Telomere Ends
- Telomere Maintenance
- Chromosome Maintenance
- Cell Cycle
- Regulation of Telomerase
Biological Process
- negative regulation of protein ADP-ribosylation
- telomere capping
- telomere assembly
- negative regulation of telomere maintenance via telomerase
- negative regulation of epithelial cell proliferation
Molecular Function
- DNA binding
- protein binding
- telomeric DNA binding
Cellular Component
- chromosome, telomeric region
- nuclear telomere cap complex
- nuclear chromosome, telomeric region
- nucleoplasm
- perinucleolar chromocenter
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000267415
- Coding exons
- 9
- Length
- 3032
- Individuals with no LoFs
- 124785
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 124795
- p
- 0.0000401
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.725 | 203 | 234 | 0.867 | 0.0000117 | 2870 |
| Missense (PolyPhen) | 12 | 15.012 | 0.79936 | 173 | ||
| Synonymous | -1.71 | 117 | 95.7 | 1.22 | 0.00000487 | 954 |
| Loss of Function | 2.76 | 9 | 23.4 | 0.385 | 0.00000130 | 250 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Plays a role in shelterin complex assembly. Isoform 1 may have additional role in tethering telomeres to the nuclear matrix. {ECO:0000269|PubMed:16166375, ECO:0000269|PubMed:16880378}.;
- Disease
- DISEASE: Dyskeratosis congenita, autosomal dominant, 3 (DKCA3) [MIM:613990]: 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:18252230}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dyskeratosis congenita, autosomal dominant, 5 (DKCA5) [MIM:268130]: A disease characterized by bone marrow hypoplasia, nail dystrophy, fine sparse hair, fine reticulate skin pigmentation, oral leukoplakia, bilateral exudative retinopathy, cerebellar hypoplasia, and growth retardation. {ECO:0000269|PubMed:18252230}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.107
Intolerance Scores
- LoFtool
- 0.146
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |