Human Gene Module / Chromosome 19 / UNC13A

UNC13Aunc-13 homolog A

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
8 / 11
Rare Variants / Common Variants
17 / 0
Aliases
UNC13A, Munc13-1
Associated Syndromes
-
Chromosome Band
19p13.11
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Molecular Function

Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Also involved in secretory granule priming in insulin secretion.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to UNC13A (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders Lim ET , et al. (2013) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Primary Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder Lipstein N , et al. (2017) Yes -
4 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test Lionel AC , et al. (2017) No -
5 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
6 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
7 Recent Recommendation A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia Luo Y et al. (2020) Yes -
8 Support - Rodin RE et al. (2021) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Sheth F et al. (2023) Yes DD, ID
11 Support - Axel Schmidt et al. (2024) No Stereotypy
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4197+7C>T - splice_region_variant Familial - - 32778826 Luo Y et al. (2020)
c.3409C>T p.Arg1137Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4484G>A p.Arg1495His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.834G>A p.Glu278%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1647G>A p.Ser549%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.154G>A p.Glu52Lys missense_variant Unknown - - 28771251 Lionel AC , et al. (2017)
c.4781G>A p.Trp1594Ter stop_gained De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.3428C>A p.Ala1143Glu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.4787C>G p.Pro1596Arg missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.4811+2_4811+3del - splice_site_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1800del p.Asn600LysfsTer32 frameshift_variant Familial - - 32778826 Luo Y et al. (2020)
c.4379C>T p.Ala1460Val missense_variant De novo - Unknown 31130284 Monies D , et al. (2019)
c.2441C>T p.Pro814Leu missense_variant De novo - Simplex 28192369 Lipstein N , et al. (2017)
c.70G>A p.Val24Met missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.4197+7C>T - splice_site_variant Familial Both parents Multiplex 23352160 Lim ET , et al. (2013)
c.1082_1083insAGGAGG p.Arg361_Glu362insGlyGly inframe_insertion Unknown - Unknown 31130284 Monies D , et al. (2019)
ENSG00000130477:ENST00000552293:exon20:c.G2425A:p.E809K,ENSG00000130477:ENST00000428389:exon21:c.G26 - missense_variant De novo - - 33432195 Rodin RE et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

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

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

1/1/2021
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
7/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Reports Added
[A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

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

Decreased from 4S to 4S

Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
7/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Reports Added
[Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.2017]
1/1/2017
icon
4S

Increased from to 4S

Description

A de novo missense variant in the UNC13A gene (p.Pro814Leu) was identified in a 6-year-old diagnosed with ASD and comorbid ADHD and presenting with developmental delay and a dyskinetic movement disorder in Lipstein et al., 2017. Functional analysis in murine neuronal cultures and C. elegans demonstrated that this variant resulted in a gain-of-function effect characterized by increased fusion propensity of synaptic vesicles, leading to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity.

Krishnan Probability Score

Score 0.53247084884729

Ranking 1521/25841 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 0.99998671101361

Ranking 478/18225 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 0.903

Ranking 137/239 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 0.94448784395938

Ranking 16095/18665 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 0.49502564240427

Ranking 559/20870 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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