ADD3
protein-codingadducin 3, the group of Adducin family
Gene summary
Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma. The three subunits are encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. While adducins alpha and gamma are ubiquitously expressed, the expression of adducin beta is restricted to brain and hematopoietic tissues. Adducin, originally purified from human erythrocytes, was found to be a heterodimer of adducins alpha and beta. Polymorphisms resulting in amino acid substitutions in these two subunits have been associated with the regulation of blood pressure in an animal model of hypertension. Heterodimers consisting of alpha and gamma subunits have also been described. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known. [provided by RefSeq, Jul 2008]
- ADDL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~139.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014862
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014862
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100516
Submitter: ClinGen
ADD3 is the γ-subunit of Adducin; a heterodimeric protein that provides structural support and maintains cytoskeletal interactions between actin and spectrin within neuronal structures. ADD3 was first reported in relation to cerebral palsy, spastic quadriplegic, 3 in 2013 (Kruer et al., PMID:23836506). It is characterized by spastic quadriplegia/diplegia, cognitive impairment, speech impairment, strabismus, and borderline to true microcephaly in infancy. Other less common phenotypes include facial dysmorphisms, cataracts, and neuroimaging abnormalities; the latter including white matter hyperintensities, anomalies of the corpus callosum, and grey matter heterotopia. The aforementioned disease entities have been grouped together as one disease entity: Complex neurodevelopmental disorder with motor features (MONDO: 0100516). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 6 POINTS. 5 unique missense variants that have been reported in 5 probands in 3 publications (PMID: 23836506, 30369941, 29768408) are included in this curation. This gene-disease association is also supported by a Drosophila model, where knockdown resulted in impaired locomotion, deficient climbing ability, and lesions in the brain lamina and medulla (PMID: 23836506). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish a definitive relationship, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on August 15, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014862
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0016215
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ADD3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016824.5. 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 | 47 | 49 | |||
| missense | 1 | 154 | 9 | 3 | 167 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 1 | 162 | 56 | 3 | 222 |
Highest pathogenic variant AF is 0.000008673844
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_058432.1 | 14 | MANE Select | |
| Ensembl | ENSP00000348381.4 | 14 | MANE Select | |
| RefSeq | NP_001112.2 | 13 | Standard | |
| RefSeq | NP_001307520.1 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| add3a | Danio rerio | Structure: intrahepatic bile duct Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Transport of small molecules
- Miscellaneous transport and binding events
Biological Process
- barbed-end actin filament capping
- actin filament bundle assembly
- transmembrane transport
Molecular Function
- structural molecule activity
- structural constituent of cytoskeleton
- calmodulin binding
- spectrin binding
- actin filament binding
Cellular Component
- condensed nuclear chromosome
- nucleoplasm
- cytosol
- cytoskeleton
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356080
- Coding exons
- 14
- Length
- 139198
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125741
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.330 | 363 | 381 | 0.952 | 0.0000191 | 4638 |
| Missense (PolyPhen) | 110 | 134.5 | 0.81785 | 1650 | ||
| Synonymous | -0.103 | 135 | 133 | 1.01 | 0.00000684 | 1348 |
| Loss of Function | 5.04 | 4 | 37.2 | 0.108 | 0.00000207 | 430 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00094 | 0.00092 | rare |
| Latino/Admixed American | 0.00015 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Plays a role in actin filament capping (PubMed:23836506). Binds to calmodulin. {ECO:0000269|PubMed:23836506}.;
- Disease
- DISEASE: Cerebral palsy, spastic quadriplegic 3 (CPSQ3) [MIM:617008]: A form of cerebral palsy, a group of non-progressive disorders of movement and/or posture resulting from defects in the developing central nervous system. CPSQ3 is an autosomal recessive neurodevelopmental disorder characterized by variable spasticity and cognitive impairment. {ECO:0000269|PubMed:23836506}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.153
Intolerance Scores
- LoFtool
- 0.209
- RVIS EVS
- 0.16
- RVIS percentile EVS
- 64.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.190
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |