MAT1A
protein-codingmethionine adenosyltransferase 1A
Gene summary
This gene catalyzes a two-step reaction that involves the transfer of the adenosyl moiety of ATP to methionine to form S-adenosylmethionine and tripolyphosphate, which is subsequently cleaved to PPi and Pi. S-adenosylmethionine is the source of methyl groups for most biological methylations. The encoded protein is found as a homotetramer (MAT I) or a homodimer (MAT III) whereas a third form, MAT II (gamma), is encoded by the MAT2A gene. Mutations in this gene are associated with methionine adenosyltransferase deficiency. [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 ~17.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0009607
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009607
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: ClinGen
The relationship between MAT1A and methionine adenosyltransferase deficiency was evaluated using the ClinGen Clinical Validity Framework as of August 15th, 2019. Methionine adenosyltransferase catalyzes a two-step reaction in which the adenosyl group of ATP is transferred to methionine to form S-adenosylmethionine, a methyl donor, and tripolyphosphate. Individuals with methionine adenosyltransferase deficiency present with persistently elevated levels of plasma methionine. Most patients with this condition are identified with hypermethioninemia on newborn screening. Follow up testing reveals normal or mildly elevated homocysteine, ruling out homocystinuria, and normal tyrosine, ruling out tyrosinemia. Most individuals with methionine adenosyltransferase deficiency have no symptoms, although some patients have developed demyelination of the brain and other abnormalities (Nashabat et al, 2018, PMID 29440907). Biallelic variants in MAT1A causing methionine adenosyltransferase were first reported by Ubagai et al in 1995 (PMID 7560086). Data from 17 patients who are homozygous or compound heterozygous for MAT1A variants were curated, including 21 unique variants (missense, nonsense, frameshift, and splicing) from 8 publications (Ubagai et al, 1995, PMID 7560086; Chamberlin et al, 1996, PMID 8770875; Hazelwood et al, 1998, PMID 9482646; Linneback et al, 2005, PMID 16435220; Fernández-Irigoyen et al, 2010, PMID 20675163; Hirabayashi et al, 2013, PMID 23973726; Nagao et al, 2013, PMID 24231718; Kim et al, 2016, PMID 26933843). More data are available but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of methionine adenosyltransferase, which is consistent with the finding of persistently elevated methionine levels in patients with this condition (Cantoni, 1951, PMID 14832292; Mudd, 1962, PMID 14476836), and a knock out mouse model (Lu et al, 2001; PMID 11320206). In summary, MAT1A is definitively associated with autosomal recessive methionine adenosyltransferase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on September 13th, 2019. Of note, while most individuals who are heterozygous for variants causing autosomal recessive methionine adenosyltransferase deficiency have normal methionine levels, some variants are reported to cause hypermethioninemia in the heterozygous state, although the level of methionine is lower than that seen in individuals who have biallelic variants in MAT1A (Kim et al, 2016; PMID 26933843). The most commonly reported variant, c.791G>A (p.Arg264His), has been shown to segregate with hypermethioninemia is an autosomal dominant manner. This variant disrupts the normal dimerization of methionine adenosyltransferase and therefore appears to act as a dominant-negative (Chamberlin et al, 1997, PMID 9042912).
Inheritance Pattern: AD
Disease ID:MONDO:0009607
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009607
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009607
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: While the disorders frequently do not have severe sequelae, and therapy may not be required for many individuals, in some, dietary measures (eg, methionine restriction) may be beneficial; AdoMet therapy has also been described as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MAT1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000429.3. 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 | 63 | 3 | 66 | |||
| missense | 14 | 22 | 159 | 4 | 199 | |
| nonsense | 4 | 2 | 6 | |||
| start loss | 0 | |||||
| frameshift | 7 | 1 | 8 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 1 | 4 | ||
| Total | 26 | 25 | 162 | 67 | 3 | 283 |
Highest pathogenic variant AF is 0.0000557636
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000420.1 | 9 | MANE Select | |
| Ensembl | ENSP00000361287.3 | 9 | MANE Select | |
| Ensembl | ENSP00000414961.1 | 5 | Standard | |
| Ensembl | ENSP00000541678.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cysteine and methionine metabolism - Homo sapiens (human)
- Vitamin B12 Metabolism
- Folate Metabolism
- One Carbon Metabolism
- Trans-sulfuration and one carbon metabolism
Biological Process
- sulfur amino acid metabolic process
- selenium compound metabolic process
- S-adenosylmethionine biosynthetic process
- one-carbon metabolic process
- methionine catabolic process
Molecular Function
- methionine adenosyltransferase activity
- ATP binding
- identical protein binding
- metal ion binding
- selenomethionine adenosyltransferase activity
Cellular Component
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372213
- Coding exons
- 9
- Length
- 17865
- Individuals with no LoFs
- 125728
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 125748
- p
- 0.0000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.65 | 166 | 238 | 0.698 | 0.0000157 | 2576 |
| Missense (PolyPhen) | 53 | 108.73 | 0.48745 | 1142 | ||
| Synonymous | -0.912 | 107 | 95.7 | 1.12 | 0.00000708 | 788 |
| Loss of Function | 2.16 | 8 | 17.8 | 0.449 | 8.66e-7 | 208 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate. {ECO:0000269|PubMed:10677294}.;
- Disease
- DISEASE: Methionine adenosyltransferase deficiency (MATD) [MIM:250850]: An inborn error of metabolism resulting in isolated hypermethioninemia. Most patients have no clinical abnormalities, although some neurologic symptoms may be present in rare cases with severe loss of methionine adenosyltransferase activity. {ECO:0000269|PubMed:10677294, ECO:0000269|PubMed:7560086, ECO:0000269|PubMed:8770875, ECO:0000269|PubMed:9042912}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.376
Intolerance Scores
- LoFtool
- 0.0748
- RVIS EVS
- -0.78
- RVIS percentile EVS
- 12.77
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.770
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |