MACF1
protein-codingmicrotubule actin crosslinking factor 1, the group of EF-hand domain containing|Plakins
Gene summary
This gene encodes a large protein containing numerous spectrin and leucine-rich repeat (LRR) domains. The encoded protein is a member of a family of proteins that form bridges between different cytoskeletal elements. This protein facilitates actin-microtubule interactions at the cell periphery and couples the microtubule network to cellular junctions. Alternative splicing results in multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, May 2013]
- KIAA0754
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~405.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032677
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032677
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0032677
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0019587
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100472
Submitter: ClinGen
Heterozygous de novo variants in MACF1 gene were first identified in 2018 (PMID: 30471716) in 9 individuals with lissencephaly, complex brain malformations, global developmental delay, severe intellectual development disorder, axial hyptonia, seizures, dysphagia, strabismus, stereotypies and involuntary movements. In this publication 8 variants were missense and affecting the GAR domain (3 of which recurrent) and one was an in-frame deletion. In 2021 (PMID: 33511591) another proband with a recurrent de novo missense variant was also described and had the same phenotype. One single report for autosomal recessive inheritance (PMID: 32010038) in two affected brothers with brain malformations, epilepsy and severe developmental delay was not included for the purposes of this curation. Other data about patients harboring variants of this gene and clinical characteristics of schizophrenia (PMID: 26666178), bipolar disorder (PMID: 34100076, 30772743) and sagittal craniosynostosis (PMID: 28808027) were also excluded. In addition, an intragenic duplication (involving exons 1-35 of MACF1) was not scored because it was found in a family with variable neuromuscular symptoms, without mention of any brain malformations, and inherited from a mildly symptomatic mother to three of her four children; two of which had severe symptoms (PMID: 24899269). MACF1 belongs to spectraplakins and acts as cytoskeletal crosslinker by coordinating with microfilaments, microtubules and intermediate filaments. It is involved in multiple neural processes including neurite outgrowth and neuronal migration. Structurally contains two calponin-homology domains, a plakin domain, a long spectrin-repeat rod domain, two calcium-binding EF-hand domains, a zinc-binding GAR domain (microtubule binding and stabilization), a positively charged Gly-Ser-Arg region and an EB1-binding domain. This gene produces 6 different isoforms via alternative splicing and differential promoter usage. The gene-disease relationship is also supported by the fact that MACF1 is required for dendritic arborization and axon outgrowth in the developing brain (PMID: 26526844) and that it acts as a positive regulator in the Wnt pathway (PMID:16815997). In summary, MACF1 is moderately associated with autosomal dominant Lissencephaly spectrum disorder with complex brainstem malformation. This was approved by the ClinGen Brain Malformation GCEP on July 25, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0032677
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0032677
Submitter: PanelApp Australia
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 MACF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001394062.1. 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 | 15 | 346 | 15 | 376 | ||
| missense | 3 | 11 | 952 | 504 | 23 | 1493 |
| nonsense | 1 | 1 | 49 | 51 | ||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 35 | 38 | ||
| splice donor/acceptor (+/-2bp) | 4 | 37 | 41 | |||
| Total | 5 | 18 | 1088 | 850 | 38 | 1999 |
Highest pathogenic variant AF is 0.0000068439617
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001380991.1 | 101 | MANE Select | |
| Ensembl | ENSP00000455274.1 | 101 | MANE Select | |
| RefSeq | NP_001384402.1 | 41 | Standard | |
| RefSeq | NP_036222.3 | 93 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| macf1a | Danio rerio | Structure: unfertilized egg Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- WNT-Ncore
- Mesodermal Commitment Pathway
Biological Process
- regulation of epithelial cell migration
- Wnt signaling pathway
- positive regulation of Wnt signaling pathway
- regulation of cell migration
- regulation of microtubule-based process
Molecular Function
- RNA binding
- actin binding
- structural molecule activity
- calcium ion binding
- protein binding
Cellular Component
- cytoplasm
- Golgi apparatus
- cytoskeleton
- microtubule
- intermediate filament
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000545844
- Coding exons
- 93
- Length
- 405862
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125748
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.43 | 2325 | 2.84e+3 | 0.819 | 0.000160 | 35716 |
| Missense (PolyPhen) | 835 | 1175.4 | 0.71042 | 14923 | ||
| Synonymous | -0.627 | 1077 | 1.05e+3 | 1.02 | 0.0000544 | 10277 |
| Loss of Function | 15.6 | 18 | 319 | 0.0565 | 0.0000186 | 3469 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000068 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Isoform 2: F-actin-binding protein which plays a role in cross-linking actin to other cytoskeletal proteins and also binds to microtubules (PubMed:15265687, PubMed:20937854). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Acts as a positive regulator of Wnt receptor signaling pathway and is involved in the translocation of AXIN1 and its associated complex (composed of APC, CTNNB1 and GSK3B) from the cytoplasm to the cell membrane (By similarity). Has actin-regulated ATPase activity and is essential for controlling focal adhesions (FAs) assembly and dynamics (By similarity). Interaction with CAMSAP3 at the minus ends of non- centrosomal microtubules tethers microtubules minus-ends to actin filaments, regulating focal adhesion size and cell migration (PubMed:27693509). May play role in delivery of transport vesicles containing GPI-linked proteins from the trans-Golgi network through its interaction with GOLGA4 (PubMed:15265687). Plays a key role in wound healing and epidermal cell migration (By similarity). Required for efficient upward migration of bulge cells in response to wounding and this function is primarily rooted in its ability to coordinate microtubule dynamics and polarize hair follicle stem cells (By similarity). {ECO:0000250|UniProtKB:Q9QXZ0, ECO:0000269|PubMed:15265687, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:27693509}.;
Intolerance Scores
- LoFtool
- 0.458
- RVIS EVS
- -3.92
- RVIS percentile EVS
- 0.21
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.950
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |