Human Gene Module / Chromosome 12 / RPH3A

RPH3Arabphilin 3A

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
Angelman syndrome
Chromosome Band
12q24.13
Associated Disorders
-
Relevance to Autism

Pavinato et al., 2023 reported six individuals with heterozygous RPH3A missense variants: four individuals with intellectual disability and epileptic seizures, and two individuals with autism spectrum disorder and intellectual disability. Additional functional assessment in this report found that both the ID/epilepsy-associated p.Thr450Ser variant and the ASD/ID-associated p.Asn618Ser variant resulted in reduced synaptic localization of GluN2A, increased GluN2A-dependent NMDAR currents, and alteration of postsynaptic calcium levels in neuronal cultures. A de novo loss-of-function variant and multiple de novo missense variants in the RPH3A gene have also been reported in ASD probands (Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020; Trost et al., 2022; Wang et al., 2023). Avagliano Trezza et al., 2021 identified RPH3A as a ubiquitination target of UBE3A and demonstrated that an Angelman syndrome-associated missense variant in UBE3A abrogated the interaction with RPH3A.

Molecular Function

The protein encoded by this gene plays an essential role in docking and fusion steps of regulated exocytosis. At the presynaptic level, RPH3A is recruited by RAB3A to the synaptic vesicle membrane in a GTP-dependent manner where it modulates synaptic vesicle trafficking and calcium-triggered neurotransmitter release. In the post-synaptic compartment, RPH3A forms a ternary complex with GRIN2A and DLG4 and regulates NMDA receptor stability.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RPH3A (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support 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 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Avagliano Trezza R et al. (2021) No -
5 Support - Trost B et al. (2022) Yes -
6 Support - Wang J et al. (2023) Yes -
7 Primary - Pavinato L et al. (2023) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.938A>G p.Gln313Arg missense_variant De novo - - 36368308 Trost B et al. (2022)
c.1717C>T p.Arg573Cys missense_variant De novo - - 36368308 Trost B et al. (2022)
c.780C>T p.Ser260%3D synonymous_variant De novo - - 36368308 Trost B et al. (2022)
c.1109G>C p.Arg370Pro missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1042C>T p.Arg348Ter stop_gained De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.686A>T p.Tyr229Phe missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.289C>T p.Arg97Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.219G>T p.Gln73His missense_variant De novo - Simplex 37403762 Pavinato L et al. (2023)
c.626G>A p.Arg209Lys missense_variant Unknown - Simplex 37403762 Pavinato L et al. (2023)
c.705G>T p.Arg235Ser missense_variant Unknown - Simplex 37403762 Pavinato L et al. (2023)
c.1853A>G p.Asn618Ser missense_variant De novo - Simplex 37403762 Pavinato L et al. (2023)
c.1349C>G p.Thr450Ser missense_variant De novo - Multiplex 37403762 Pavinato L et al. (2023)
c.1524G>C p.Gln508His missense_variant Unknown Not maternal Simplex 37403762 Pavinato L et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

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.

7/1/2023
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.56834612193929

Ranking 1120/25841 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 0.73860347806591

Ranking 4274/18225 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 0.86594078935675

Ranking 4109/18665 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 0.080112414776044

Ranking 6550/20870 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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