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 / 10
Rare Variants / Common Variants
15 / 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.

SFARI Genomic Platforms
Reports related to UNC13A (10 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
Rare Variants   (15)
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.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

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.

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.

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.

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.

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.

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.

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.
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
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
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).
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.
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