MCAT
protein-codingmalonyl-CoA-acyl carrier protein transacylase
Gene summary
The protein encoded by this gene is found exclusively in the mitochondrion, where it catalyzes the transfer of a malonyl group from malonyl-CoA to the mitochondrial acyl carrier protein. The encoded protein may be part of a fatty acid synthase complex that is more like the type II prokaryotic and plastid complexes rather than the type I human cytosolic complex. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014753
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0957935
Submitter: ClinGen
*MCAT* was first reported in relation to autosomal recessive optic atrophy 15 (MIM #620583) in 2020 (Li et al., PMID: 31915829). At least four variants (missense and frameshift) have been reported in two probands in two publications (PMID: 31915829, PMID: 33918393). One proband has a brother who shares the genotype and phenotype, but no other segregations are available from this family to enable scoring of co-segregation. Variants in *MCAT* have been reported in individuals with autosomal recessive optic atrophy 15 and one proband asserted to have combined oxidative phosphorylation deficiency. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found insufficient evidence of difference in molecular mechanism or inheritance pattern despite phenotypic variability of the probands. The combined oxidative phosphorylation deficiency case reported in Webb et. al 2023 is known to the group and was reviewed as a part of lumping and splitting (PMID:36881526). Although there is insufficient evidence to split the entities, the Webb case is not scored in this curation due to a lack of information about the ocular phenotype. Furthermore, the age of the proband at the time of the report and this curation is younger than the expected age of onset for the disease. This gene-disease relationship is supported by functional alteration experimental evidence and a mouse model (PMID: 31915829). The effects of overexpression of the individual variant and variant pair in HEK293T cells was monitored through immunostaining and immunoelectron microscopy demonstrating that the mitochondria of cells transfected with either *MCAT* Leu81Arg and *MCAT* Leu81Arg/Arg212Trp were thinner than those of wild type *MCAT* cells. This showed that the expression of the mutants had a damaging effect on mitochondrial inner membrane morphology (PMID: 31915829). An *MCAT* floxed mouse (MCATt-Flox+/+, PMID: 23077570) was treated with adeno-associated virus 2 (AAV2)-Cre to knock out *MCAT* specifically in retinal ganglion cells. The results showed that depletion of *MCAT* expression in the mitochondria of the retinal ganglion cells disrupts maintenance of retinal ganglion cell axons, helping to explain a disruption in the relevant tissue observed in human probands (PMID: 31915829). In summary, there is limited evidence to support the gene-disease relationship between *MCAT* and optic atrophy 15. Although more evidence from cases with *MCAT* variants will be needed to support a more definitive classification, no convincing evidence has yet emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on May 16th, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0957935
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
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 MCAT variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_173467.5. 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 | 3 | 1 | 4 | |||
| missense | 1 | 53 | 6 | 2 | 62 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 2 | 1 | 55 | 9 | 3 | 70 |
Highest pathogenic variant AF is 0.000020070705
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_775738.3 | 4 | MANE Select | |
| Ensembl | ENSP00000290429.5 | 4 | MANE Select | |
| RefSeq | NP_055322.1 | 3 | Standard | |
| Ensembl | ENSP00000331306.5 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fatty acid biosynthesis - Homo sapiens (human)
- Metabolism of lipids
- Mitochondrial Fatty Acid Beta-Oxidation
- Metabolism
- Fatty acid metabolism
Biological Process
- fatty acid biosynthetic process
- fatty acid beta-oxidation
Molecular Function
- RNA binding
- fatty acid synthase activity
- [acyl-carrier-protein] S-malonyltransferase activity
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000290429
- Coding exons
- 4
- Length
- 11189
- Individuals with no LoFs
- 125699
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 49
- Defined
- 125748
- p
- 0.000195
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.291 | 202 | 214 | 0.944 | 0.0000120 | 2471 |
| Missense (PolyPhen) | 83 | 89.661 | 0.9257 | 996 | ||
| Synonymous | -0.767 | 105 | 95.5 | 1.10 | 0.00000609 | 820 |
| Loss of Function | 1.19 | 7 | 11.3 | 0.619 | 5.68e-7 | 136 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00025 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the transfer of a malonyl moiety from malonyl- CoA to the free thiol group of the phosphopantetheine arm of the mitochondrial ACP protein (NDUFAB1). This suggests the existence of the biosynthesis of fatty acids in mitochondria. {ECO:0000269|PubMed:12882974}.;
Recessive Scores
- pRec
- 0.318
Intolerance Scores
- LoFtool
- 0.538
- RVIS EVS
- -0.05
- RVIS percentile EVS
- 50.34
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.695
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |