MMAA
protein-codingmetabolism of cobalamin associated A
Gene summary
The protein encoded by this gene is involved in the translocation of cobalamin into the mitochondrion, where it is used in the final steps of adenosylcobalamin synthesis. Adenosylcobalamin is a coenzyme required for the activity of methylmalonyl-CoA mutase. Defects in this gene are a cause of methylmalonic aciduria. [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 ~61.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: ClinGen
The relationship between MMAA and methylmalonic aciduria, cblA type, was evaluated using the ClinGen Clinical Validity Framework as of January 7, 2021. The clinical presentation varies, but the condition is characterized by recurrent vomiting, lethargy, seizures, metabolic acidosis, and developmental delay. Patients are responsive to treatment with Vitamin B12 (Hörster, et al, 2007, PMID: 17597648). Bilallelic variants in MMAA were first reported in humans with methylmalonic academia (MMA) in 2002 (Dobson et al, PMID 12438653). Since then, about 60 different variants in MMAA have been published (Plessl et al, 2017, PMID 28497574), including p.Arg145Ter which accounts for about 43% of disease-causing variants (Lerner-Ellis et al, 2004, PMID 15523652). Evidence supporting this gene-disease relationship includes case-level and experimental data. Seven unique variants (nonsense, frameshift, missense) from 8 probands from 4 publications were curated (Lerner-Ellis et al, 2004, PMID 15523652; Keyfi et al, 2016, PMID 28536607; Plessl et al, 2017, PMID 28497574; Lin et al, 2018, PMID 29996803). Further evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The gene-disease relationship is supported by the biochemical function of MMAA (Takahashi-Iñiguez et al, 2017, PMID 28943303), it’s physical interaction with methylmalonyl CoA mutase (MUT) which is encoded by another gene involved in methylmalonic acidemia (Froese et al, 2010), and functional alteration studies (Plessl et al, 2017, PMID 28497574). In summary, MMAA is definitively associated with methylmalonic aciduria, cblA type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009613
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Hematologic; Neurologic; Ophthalmologic
Intervention: Biochemical
Rationale: Long-term dietary (high-calorie diet low in propiogenic amino acid precursors with carnitine supplementation) and medical management (eg, IM hydroxocobalamin, antibiotics to decrease propionate production) is indicated; Fasting and high-protein consumption should be avoided; In the emergent setting, prompt recognition and appropriate metabolic care may be beneficial to decrease morbidity and mortality; Antioxidants for optic nerve atrophy may be beneficial; Liver/kidney transplant has been described in methylmalonic acidemia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MMAA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_172250.3. 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 | 5 | 149 | 1 | 155 | ||
| missense | 7 | 18 | 156 | 7 | 188 | |
| nonsense | 24 | 20 | 1 | 45 | ||
| start loss | 1 | 1 | ||||
| frameshift | 35 | 35 | 1 | 71 | ||
| splice donor/acceptor (+/-2bp) | 17 | 4 | 21 | |||
| Total | 66 | 91 | 167 | 156 | 1 | 481 |
Highest pathogenic variant AF is 0.0003930974
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_758454.1 | 6 | MANE Select | |
| Ensembl | ENSP00000497008.1 | 6 | MANE Select | |
| RefSeq | NP_001362573.1 | 6 | Standard | |
| Ensembl | ENSP00000427422.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Metabolism of lipids
- Propionyl-CoA catabolism
- Mitochondrial Fatty Acid Beta-Oxidation
- Cobalamin (Cbl, vitamin B12) transport and metabolism
- Metabolism
Biological Process
- cobalamin metabolic process
- cobalamin biosynthetic process
Molecular Function
- GTPase activity
- protein binding
- GTP binding
- identical protein binding
- protein homodimerization activity
Cellular Component
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000281317
- Coding exons
- 6
- Length
- 41773
- Individuals with no LoFs
- 125633
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 114
- Defined
- 125747
- p
- 0.000453
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.331 | 209 | 223 | 0.938 | 0.0000116 | 2685 |
| Missense (PolyPhen) | 58 | 75.362 | 0.76962 | 881 | ||
| Synonymous | 0.132 | 80 | 81.5 | 0.981 | 0.00000412 | 845 |
| Loss of Function | 0.494 | 20 | 22.5 | 0.888 | 0.00000145 | 244 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00071 | 0.00071 | rare |
| South Asian | 0.00043 | 0.00042 | rare |
| Other | 0.00066 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: GTPase, binds and hydrolyzes GTP (PubMed:28497574, PubMed:20876572). Involved in intracellular vitamin B12 metabolism, mediates the transport of cobalamin (Cbl) into mitochondria for the final steps of adenosylcobalamin (AdoCbl) synthesis. Functions as a G-protein chaperone that assists AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase (MUT) and reactivation of the enzyme during catalysis (PubMed:28497574, PubMed:20876572). {ECO:0000269|PubMed:20876572, ECO:0000269|PubMed:28497574}.;
Recessive Scores
- pRec
- 0.0990
Intolerance Scores
- LoFtool
- 0.293
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 15.12
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.164
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |