Human Gene Module / Chromosome 4 / METTL14

METTL14methyltransferase 14, N6-adenosine-methyltransferase non-catalytic subunit

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
6 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4q26
Associated Disorders
-
Relevance to Autism

In a report demonstrating that modification of APC with N6-methyladenosine faciliated its translation in neuronal somata via YTH domain-containing family M6A reader proteins, Broix et al. 2025 found that overexpression of the M6A writer METTL14 containing human missense variants associated with autism or schizophrenia impaired the transport and local translation of APC-regulated target mRNA beta-actin in axons and growth cones, which subsequently hindered axon development. In addition to the functionally validated ASD-associated missense variant (originally identified in an ASD proband from the Autism Sequencing Consortium in Neale et al., 2012), three additional de novo missense variants have been identified in ASD probands, including a variant predicted to be damaging by CADD and REVEL in an MSSNG proband (Zhou et al., 2022; Fu et al., 2022; Yuan et al., 2023). Depletion by Mettl14 knockout in embryonic mouse brains was previously reported to prolong the cell cycle of radial glia cells and extend cortical neurogenesis into postnatal stages, demonstrating its importance in the regulation of mammalian brain development (Yoon et al., 2017).

Molecular Function

Enables mRNA binding activity and mRNA m(6)A methyltransferase activity. Involved in mRNA modification; mRNA splicing, via spliceosome; and mRNA stabilization. Located in nucleoplasm. Part of RNA N6-methyladenosine methyltransferase complex.

External Links
Gene CardPubMed
Human
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SFARI Genomic Platforms
GPF browser
Reports related to METTL14 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Support De novo mutations in schizophrenia implicate synaptic networks Fromer M , et al. (2014) No -
3 Support - Ki-Jun Yoon et al. (2017) No -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Fu JM et al. (2022) Yes -
7 Support - Yuan B et al. (2023) Yes -
8 Primary - Loic Broix et al. () Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.117T>A p.Asp39Glu missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.1247G>A p.Gly416Glu missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.1028G>A p.Arg343His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.931A>G p.Ile311Val missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.1196C>T p.Ser399Leu missense_variant De novo - Simplex 24463507 Fromer M , et al. (2014)
c.739-1G>T p.? splice_site_variant Familial Paternal Simplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.41291657199376

Ranking 21975/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.84716577504365

Ranking 3634/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.68928333441517

Ranking 1092/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.16469231950737

Ranking 4901/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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