METTL3
methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit, the group of m6A methyltransferase complex|7BS N6-adenosine DNA/RNA methyltransferases
Basic information
Region (hg38): 14:21498133-21511342
Links
Phenotypes
GenCC
Source:
No genCC data.
ClinVar
This is a list of variants' phenotypes submitted to
- not_specified (35 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the METTL3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000019852.5. Only rare variants are included in the table.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 0 | |||||
| missense | 35 | 35 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 35 | 0 | 0 |
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| METTL3 | protein_coding | protein_coding | ENST00000298717 | 11 | 13241 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.80e-7 | 0.993 | 125560 | 0 | 186 | 125746 | 0.000740 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.05 | 175 | 331 | 0.529 | 0.0000180 | 3798 |
| Missense in Polyphen | 30 | 125.4 | 0.23924 | 1450 | ||
| Synonymous | -0.237 | 124 | 121 | 1.03 | 0.00000593 | 1161 |
| Loss of Function | 2.44 | 16 | 30.6 | 0.523 | 0.00000180 | 316 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000692 | 0.000691 |
| Ashkenazi Jewish | 0.000595 | 0.000595 |
| East Asian | 0.000218 | 0.000217 |
| Finnish | 0.000647 | 0.000647 |
| European (Non-Finnish) | 0.00111 | 0.00111 |
| Middle Eastern | 0.000218 | 0.000217 |
| South Asian | 0.000457 | 0.000457 |
| Other | 0.000979 | 0.000978 |
dbNSFP
Source:
- Function
- FUNCTION: The METTL3-METTL14 heterodimer forms a N6- methyltransferase complex that methylates adenosine residues at the N(6) position of some RNAs and regulates various processes such as the circadian clock, differentiation of embryonic and haematopoietic stem cells, cortical neurogenesis, response to DNA damage, differentiation of T-cells and primary miRNA processing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:27627798, PubMed:27373337, PubMed:27281194, PubMed:28297716, PubMed:29506078, PubMed:29348140, PubMed:9409616). In the heterodimer formed with METTL14, METTL3 constitutes the catalytic core (PubMed:27627798, PubMed:27373337, PubMed:27281194). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability, processing, translation efficiency and editing (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:28297716, PubMed:9409616). M6A acts as a key regulator of mRNA stability: methylation is completed upon the release of mRNA into the nucleoplasm and promotes mRNA destabilization and degradation (PubMed:28637692). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A regulates the length of the circadian clock: acts as an early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). Involved in the response to DNA damage: in response to ultraviolet irradiation, METTL3 rapidly catalyzes the formation of m6A on poly(A) transcripts at DNA damage sites, leading to the recruitment of POLK to DNA damage sites (PubMed:28297716). M6A is also required for T-cell homeostasis and differentiation: m6A methylation of transcripts of SOCS family members (SOCS1, SOCS3 and CISH) in naive T-cells promotes mRNA destabilization and degradation, promoting T-cell differentiation (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates m6A methylation of Xist RNA, thereby participating in random X inactivation: m6A methylation of Xist leads to target YTHDC1 reader on Xist and promote transcription repression activity of Xist (PubMed:27602518). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity). METTL3 mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998). Acts as a positive regulator of mRNA translation independently of the methyltransferase activity: promotes translation by interacting with the translation initiation machinery in the cytoplasm (PubMed:27117702). Its overexpression in a number of cancer cells suggests that it may participate to cancer cell proliferation by promoting mRNA translation (PubMed:27117702). {ECO:0000250|UniProtKB:Q8C3P7, ECO:0000269|PubMed:22575960, ECO:0000269|PubMed:24284625, ECO:0000269|PubMed:25719671, ECO:0000269|PubMed:25799998, ECO:0000269|PubMed:26321680, ECO:0000269|PubMed:26593424, ECO:0000269|PubMed:27117702, ECO:0000269|PubMed:27281194, ECO:0000269|PubMed:27373337, ECO:0000269|PubMed:27602518, ECO:0000269|PubMed:27627798, ECO:0000269|PubMed:28297716, ECO:0000269|PubMed:28637692, ECO:0000269|PubMed:29348140, ECO:0000269|PubMed:29506078, ECO:0000269|PubMed:9409616}.;
- Pathway
- mRNA Processing;Metabolism of RNA;Processing of Capped Intron-Containing Pre-mRNA
(Consensus)
Recessive Scores
- pRec
- 0.124
Intolerance Scores
- loftool
- 0.454
- rvis_EVS
- -0.09
- rvis_percentile_EVS
- 46.74
Haploinsufficiency Scores
- pHI
- 0.692
- hipred
- Y
- hipred_score
- 0.627
- ghis
- 0.592
Essentials
- essential_gene_CRISPR
- E
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.879
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Mettl3
- Phenotype
- mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype;
Gene ontology
- Biological process
- mRNA splicing, via spliceosome;RNA methylation;adenosine to inosine editing;mRNA processing;mRNA catabolic process;cellular response to DNA damage stimulus;spermatogenesis;circadian rhythm;dosage compensation by inactivation of X chromosome;stem cell population maintenance;forebrain radial glial cell differentiation;primary miRNA processing;cellular response to UV;gliogenesis;regulation of T cell differentiation;negative regulation of Notch signaling pathway;regulation of meiotic cell cycle;mRNA destabilization;mRNA methylation;endothelial to hematopoietic transition;regulation of hematopoietic stem cell differentiation;positive regulation of cap-independent translational initiation;primary miRNA methylation
- Cellular component
- nucleus;nucleoplasm;cytoplasm;nuclear speck;RNA N6-methyladenosine methyltransferase complex
- Molecular function
- mRNA (N6-adenosine)-methyltransferase activity;mRNA binding;protein binding;RNA methyltransferase activity;protein heterodimerization activity;S-adenosyl-L-methionine binding