Human Gene Module / Chromosome 3 / MED12L

MED12Lmediator complex subunit 12L

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
16 / 0
Aliases
MED12L, NOPAR,  TNRC11L,  TRALP,  TRALPUSH
Associated Syndromes
-
Chromosome Band
3q25.1
Associated Disorders
ASD
Relevance to Autism

Rare de novo missense variants in the MED12L gene have been observed in ASD probands from simplex families (Iossifov et al., 2014; Yuen et al., 2017). Nizon et al., 2019 described a cohort of seven individuals harboring MED12L variants that presented with developmental delay/intellectual disability; furthermore, four of these individuals also presented with autism spectrum disorder/autistic features.

Molecular Function

The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MED12L (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Recent Recommendation Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect Nizon M , et al. (2019) No ASD or autistic features
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Sheth F et al. (2023) Yes DD, ID
7 Support - Karthika Ajit Valaparambil et al. () Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 31155615 Nizon M , et al. (2019)
- - copy_number_loss De novo - - 31155615 Nizon M , et al. (2019)
- - copy_number_gain De novo - Simplex 31155615 Nizon M , et al. (2019)
c.6304-8C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.4374-1G>A - splice_site_variant Unknown - - 31155615 Nizon M , et al. (2019)
c.4686-1G>A - splice_site_variant De novo - - 31155615 Nizon M , et al. (2019)
c.5992C>T p.Gln1998Ter stop_gained Unknown - - 31155615 Nizon M , et al. (2019)
c.79C>T p.Gln27Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.3802T>C p.Cys1268Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4021C>T p.Pro1341Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2001G>C p.Glu667Asp missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.82G>A p.Asp28Asn missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1747dup p.Ser583PhefsTer8 frameshift_variant De novo - - 31155615 Nizon M , et al. (2019)
c.3743G>A p.Arg1248Lys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3713A>G p.Asp1238Gly missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.5978G>T p.Ser1993Ile missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Rare de novo missense variants in the MED12L gene have been observed in ASD probands from simplex families (Iossifov et al., 2014; Yuen et al., 2017). Nizon et al., 2019 described a cohort of seven individuals harboring MED12L variants that presented with developmental delay/intellectual disability; furthermore, four of these individuals also presented with autism spectrum disorder/autistic features.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

Rare de novo missense variants in the MED12L gene have been observed in ASD probands from simplex families (Iossifov et al., 2014; Yuen et al., 2017). Nizon et al., 2019 described a cohort of seven individuals harboring MED12L variants that presented with developmental delay/intellectual disability; furthermore, four of these individuals also presented with autism spectrum disorder/autistic features.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Rare de novo missense variants in the MED12L gene have been observed in ASD probands from simplex families (Iossifov et al., 2014; Yuen et al., 2017). Nizon et al., 2019 described a cohort of seven individuals harboring MED12L variants that presented with developmental delay/intellectual disability; furthermore, four of these individuals also presented with autism spectrum disorder/autistic features.

Reports Added
[New Scoring Scheme]
7/1/2019
icon
4S

Increased from to 4S

Description

Rare de novo missense variants in the MED12L gene have been observed in ASD probands from simplex families (Iossifov et al., 2014; Yuen et al., 2017). Nizon et al., 2019 described a cohort of seven individuals harboring MED12L variants that presented with developmental delay/intellectual disability; furthermore, four of these individuals also presented with autism spectrum disorder/autistic features.

Krishnan Probability Score

Score 0.49592641576898

Ranking 2744/25841 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 0.99999927637145

Ranking 284/18225 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
Iossifov Probability Score

Score 0.928

Ranking 114/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.94859820908799

Ranking 17749/18665 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 -0.23819590241764

Ranking 16171/20870 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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