Human Gene Module / Chromosome 6 / STXBP5

STXBP5Syntaxin binding protein 5 (tomosyn)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
20 / 0
Aliases
STXBP5, RP11-361F15.4,  LGL3,  LLGL3,  Nbla04300
Associated Syndromes
-
Chromosome Band
6q24.3
Associated Disorders
-
Relevance to Autism

Potentially damaging heterozygous missense variants in the STXBP5 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014).

Molecular Function

Plays a regulatory role in calcium-dependent exocytosis and neurotransmitter release. Inhibits membrane fusion between transport vesicles and the plasma membrane. May modulate the assembly of trans-SNARE complexes between transport vesicles and the plasma membrane. Inhibits translocation of GLUT4 from intracellular vesicles to the plasma membrane.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to STXBP5 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Novel copy number variants in children with autism and additional developmental anomalies Davis LK , et al. (2009) Yes -
2 Primary Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
6 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
7 Support - Zhou X et al. (2022) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
TC>T - frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss Familial Maternal Multiplex 21547721 Davis LK , et al. (2009)
c.2763G>A p.Lys921%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.715-1G>A - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2314G>A p.Asp772Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1080A>G p.Gln360%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3125C>T p.Ala1042Val missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.625G>A p.Gly209Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1306A>G p.Asn436Asp missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2380A>G p.Ile794Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2405C>T p.Thr802Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3053A>T p.Tyr1018Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.157C>T p.Arg53Cys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.251T>C p.Phe84Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.826A>G p.Ile276Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2405C>T p.Thr802Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3236A>T p.Gln1079Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1234C>G p.Leu412Val missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
c.1505A>G p.Tyr502Cys missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in STXBP5 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo LoF variant in STXBP5 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[New Scoring Scheme]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in STXBP5 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
icon
3

Increased from to 3

Description

A de novo LoF variant in STXBP5 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Novel copy number variants in children with autism and additional developmental anomalies.2009] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
Krishnan Probability Score

Score 0.49086569776694

Ranking 5936/25841 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 0.99999159963204

Ranking 442/18225 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 0.873

Ranking 173/239 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 0.36656780488339

Ranking 240/18665 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
Larsen Cumulative Evidence Score

Score 24.5

Ranking 80/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.58522078767312

Ranking 127/20870 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
Submit New Gene

Report an Error