Human Gene Module / Chromosome 3 / AP2M1

AP2M1adaptor related protein complex 2 subunit mu 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 9
Rare Variants / Common Variants
10 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
3q27.1
Associated Disorders
-
Relevance to Autism

Analysis of whole-exome sequencing data from 13,091 individuals diagnosed with autism recruited from the SSC, SPARK, and iPSYCH cohorts, 19,488 first-degree relatives of individuals with autism from the SSC and SPARK cohorts, and 194,070 individuals identified from unselected population samples from the iPSYCH and UK Biobank cohorts in Rolland et al., 2023 identified AP2M1 as a novel ASD candidate gene intolerant to loss-of-function variants with an odds ratio greater than 10. Several de novo variants in the AP2M1 gene, includiing a de novo loss-of-function variant and multiple de novo missense variants, have been identified in ASD probands (Yuen et al, 2017; Satterstrom et al., 2020; Zhou et al., 2022; Wang et al., 2023). A recurrent de novo missense variant in the AP2M1 gene (p.Arg170Trp) that resulted in impaired clathrin-mediated endocytosis was found to be responsible for a form of autosomal dominant intellectual disability (MRD60; OMIM 618587) in four unrelated females in Helbig et al., 2019; all four females presented with global developmental delay, moderate-severe intellectual disability, and seizures, and two of the four individuals with this disorder were also diagnosed with autism spectrum disorder.

Molecular Function

This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. The encoded protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. The encoded protein may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to AP2M1 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Kanduri C , et al. (2015) Yes -
2 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support - Helbig I et al. (2019) No ASD
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Primary - Rolland T et al. (2023) Yes -
7 Support - Wang J et al. (2023) Yes -
8 Support - Cirnigliaro M et al. (2023) Yes -
9 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Paternal - 26052927 Kanduri C , et al. (2015)
c.473A>G p.Gln158Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.490G>A p.Glu164Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.508C>T p.Arg170Trp missense_variant De novo - - 31104773 Helbig I et al. (2019)
c.502C>T p.Gln168Ter missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1220T>C p.Phe407Ser missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.822-1G>C - splice_site_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1127A>C p.Asn376Thr missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.755T>C p.Val252Ala missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.502C>T p.Arg168Trp missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Score Delta: Score remained at 2

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.

7/1/2023
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.60611134992661

Ranking 321/25841 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 0.99389317424324

Ranking 1613/18225 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 0.92952585192849

Ranking 11190/18665 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 0.17602019895769

Ranking 4688/20870 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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