MTAP
protein-codingmethylthioadenosine phosphorylase
Gene summary
This gene encodes an enzyme that plays a major role in polyamine metabolism and is important for the salvage pathway of both adenine and methionine. The encoded enzyme is deficient in many cancers. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2021]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~135.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007205
Submitter: ClinGen
MTAP (MethylThioAdenosine Phosphorylase) was first reported in relation to autosomal dominant diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH [MIM 112250]) in 2012 (Camacho-Vanegas et al., PMID: 22464254). However, prior to this the critical locus was identified through linkage (Martignetti et al 1999) and reports of the condition had been circulating since its early identification (Arnold, 1973). DMS-MFH presents with unique bone dysplasia phenotypes that result in fractures and poor healing, as well as progressive wasting, cataracts and muscular dystrophy. Approximately 35% of affected individuals develop bone sarcoma. The reported variants are synonymous (predicted silent) variants that affect splicing of the MTAP gene and result in numerous isoforms with negative consequences on MTAP functions. Evidence supporting this gene-disease relationship includes case-level, segregation and experimental data. Variants in MTAP have been reported in at least 5 probands in 1 publication (PMID:22464254) summarizing multiple prior publications. MTAP variants display a clear autosomal dominant inheritance pattern. The mechanism for disease is altered function and is still being investigated. 5.5 points (2.5 points case level data and 3 points segregation) were received in the genetic evidence section. Experimental evidence is limited to 2.75 points including expression studies including RNA analysis from patients, in vitro functional assays and has some support from a mouse model (PMIDs:19567676;22464254;11895909). In addition, around 1/3 of osteosarcomas (35%) display loss of MTAP. While heterozygous knockout of MTAP in mice does not cause osteosarcoma, these mice display T-cell lymphoma and the homozygous knockout is embryonic lethal, which indicates the essential nature of the MTAP gene. In summary, there is moderate evidence to support the relationship between MTAP and diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH).
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Oncologic
Intervention: Oncologic
Rationale: Individuals are at high risk for aggressive bone sarcoma, and surveillance and early treatment may be beneficial to reduce morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MTAP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002451.4. 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 | 1 | 5 | 2 | 8 | ||
| missense | 43 | 3 | 2 | 48 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 45 | 8 | 4 | 57 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002442.2 | 8 | MANE Select | |
| Ensembl | ENSP00000494373.1 | 8 | MANE Select | |
| RefSeq | NP_001382969.1 | 8 | Standard | |
| RefSeq | NP_001382970.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cysteine and methionine metabolism - Homo sapiens (human)
- S-Adenosylhomocysteine (SAH) Hydrolase Deficiency
- Methionine Metabolism
- Methionine Adenosyltransferase Deficiency
- Glycine N-methyltransferase Deficiency
Biological Process
- nucleobase-containing compound metabolic process
- purine ribonucleoside salvage
- nicotinamide riboside catabolic process
- L-methionine salvage from methylthioadenosine
- interleukin-12-mediated signaling pathway
Molecular Function
- phosphorylase activity
- protein binding
- S-methyl-5-thioadenosine phosphorylase activity
Cellular Component
- nucleus
- cytoplasm
- cytosol
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380172
- Coding exons
- 8
- Length
- 129105
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125746
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0176 | 167 | 166 | 1.00 | 0.00000888 | 1848 |
| Missense (PolyPhen) | 52 | 61.082 | 0.85132 | 708 | ||
| Synonymous | -1.54 | 77 | 61.7 | 1.25 | 0.00000380 | 542 |
| Loss of Function | 0.489 | 12 | 14.0 | 0.859 | 5.91e-7 | 181 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.000089 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0.000053 | 0.000046 | rare |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the reversible phosphorylation of S-methyl-5'- thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S- adenosylmethionine. Has broad substrate specificity with 6- aminopurine nucleosides as preferred substrates. {ECO:0000255|HAMAP-Rule:MF_03155, ECO:0000269|PubMed:3091600}.;
- Disease
- DISEASE: Note=Loss of MTAP activity may play a role in human cancer. MTAP loss has been reported in a number of cancers, including osteosarcoma, malignant melanoma and gastric cancer.;
Recessive Scores
- pRec
- 0.350
Intolerance Scores
- LoFtool
- 0.376
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.69
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.832
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |