ACD
protein-codingACD shelterin complex subunit and telomerase recruitment factor, the group of Shelterin complex
Gene summary
This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018045
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014690
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0100569
Submitter: ClinGen
*ACD* was first reported in relation to semidominant *ACD*-related short telomere syndrome in 2014 (Kocak et al., PMID: 25233904). *ACD* encodes one of the six core proteins of the shelterin complex that coats telomeres. This complex functions to regulate telomerase and telomere end protection (PMID: 32674474). Individuals with variants in *ACD* have variable phenotypes including oral leukoplakia, nail dystrophy, abnormal skin pigmentation, premature graying of the hair, cerebellar hypoplasia, bone marrow failure, aplastic anemia, pulmonary fibrosis, and short telomere length (PMIDs: 30064976, 30995915, 31515401). Pulmonary phenotypes have been seen both in isolation and as part of a syndromic presentation (PMID: 31515401). There is typically a pediatric age of onset for patients with a diagnosis of Hoyeraal-Hreidarsson syndrome or dyskeratosis congenita, whereas there is an adult age of onset for patients with pulmonary fibrosis. Variants in *ACD* have been reported in individuals with the following disease entities: dyskeratosis congenita, autosomal dominant 6, dyskeratosis congenita, autosomal recessive 7, Hoyeraal-Hreidarsson syndrome, hereditary isolated aplastic anemia, and pulmonary fibrosis. 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, *ACD*-related short telomere syndrome (OMIM: 616553). Of note, this gene has also been implicated in familial melanoma and long telomeres. Variants associated with long and short telomeres are distinct and the long telomere phenotype will be assessed separately. Nine variants (6 missense, 2 in-frame indels, 1 frameshift) that have been reported in 10 probands across 6 publications (PMIDs: 25233904, 25205116, 30064976, 31515401, 30995915, 33446513) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by biochemical function assays, expression studies, functional alteration assays, cell culture models, animal models, and rescue models (PMIDs: 33446513, 25205116, 27807141, 25128433, 15537664). In summary, there is definitive evidence supporting the relationship between *ACD* and semidominant *ACD*-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 February 20, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0014690
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0100569
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014690
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic; Neurologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic
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; HSCT may be indicated due to manifestations including leukemia and bone marrow failure; Awareness of infectious risk may allow prompt diagnosis and treatment of infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ACD variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001082486.2. 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 | 5 | 318 | 323 | |||
| missense | 521 | 27 | 1 | 549 | ||
| nonsense | 13 | 13 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 2 | 23 | 26 | ||
| splice donor/acceptor (+/-2bp) | 1 | 13 | 14 | |||
| Total | 1 | 3 | 576 | 345 | 1 | 926 |
Highest pathogenic variant AF is 0.0000068728145
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001075955.2 | 12 | MANE Select | |
| Ensembl | ENSP00000478084.1 | 12 | MANE Select | |
| RefSeq | NP_001397813.1 | 11 | Standard | |
| RefSeq | NP_075065.3 | 12 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| acd | Danio rerio | Structure: post-vent region Quality: curved dorsal abnormal |
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
- telomere maintenance
- skeletal system development
- urogenital system development
- intracellular protein transport
- telomere capping
Molecular Function
- protein binding
- telomeric DNA binding
- protein-containing complex binding
- DNA polymerase binding
- protein binding involved in negative regulation of telomere maintenance via telomerase
Cellular Component
- nuclear telomere cap complex
- nuclear chromosome, telomeric region
- nucleoplasm
- nuclear body
- shelterin complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000393919
- Coding exons
- 12
- Length
- 3299
- Individuals with no LoFs
- 125685
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 56
- Defined
- 125741
- p
- 0.000223
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.486 | 345 | 321 | 1.08 | 0.0000162 | 3398 |
| Missense (PolyPhen) | 55 | 73.209 | 0.75128 | 931 | ||
| Synonymous | -1.88 | 167 | 139 | 1.20 | 0.00000716 | 1218 |
| Loss of Function | 0.822 | 21 | 25.5 | 0.824 | 0.00000120 | 277 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00038 | 0.00037 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00027 | 0.00026 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0.00033 | 0.00033 | rare |
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. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by recruiting telomerase to telomeres and increasing its processivity. May play a role in organogenesis. {ECO:0000269|PubMed:15181449, ECO:0000269|PubMed:16166375, ECO:0000269|PubMed:16880378, ECO:0000269|PubMed:17237768, ECO:0000269|PubMed:20231318, ECO:0000269|PubMed:25205116, ECO:0000269|PubMed:25233904}.;
- Disease
- DISEASE: Dyskeratosis congenita, autosomal dominant, 6 (DKCA6) [MIM:616553]: 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:25205116}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dyskeratosis congenita, autosomal recessive, 7 (DKCB7) [MIM:616553]: 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:25233904}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.134
Intolerance Scores
- LoFtool
- 0.872
- RVIS EVS
- -0.6
- RVIS percentile EVS
- 18.14
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.778
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |