Human Gene Module / Chromosome 4 / SPARCL1

SPARCL1SPARC like 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
15 / 0
Aliases
SPARCL1, MAST 9,  MAST9,  PIG33,  SC1
Associated Syndromes
-
Chromosome Band
4q22.1
Associated Disorders
-
Relevance to Autism

A number of predicted loss-of-function and damaging missense variants in the SPARCL1 gene, including a de novo LoF variant, were observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). The protein encoded by the SPARCL1 gene, hevin, was shown to induce thalamocortical synapse formation by bridging neurexin 1 -alpha and neuroligin 1-beta following secretion from astrocytes (Singh et al., 2016). Functional analysis of the ASD-associated SPARCL1 p.Trp647Arg missense variant in Taketomi et al., 2022 demonstrated that this mutation impaired normal Hevin secretion and resulted in accumulation of protein in the endoplasmic reticulum, leading to activation of unfolded protein responses.

Molecular Function

Predicted to enable calcium ion binding activity; collagen binding activity; and extracellular matrix binding activity. Predicted to be involved in anatomical structure development and regulation of synapse organization. Located in extracellular space.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SPARCL1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Postmortem brain abnormalities of the glutamate neurotransmitter system in autism Purcell AE , et al. (2001) Yes -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1? and NL1 via Hevin Singh SK , et al. (2016) No -
4 Support - Taketomi T et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.151G>T p.Glu51Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.1256C>T p.Thr419Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.496C>T p.Gln166Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1462A>T p.Thr488Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1547C>T p.Thr516Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1828C>T p.His610Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1939T>C p.Trp647Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.719C>G p.Ser240Cys missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1382C>T p.Thr461Ile missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1427A>G p.Asn476Ser missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1462A>T p.Thr488Ser missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1462A>T p.Thr488Ser missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1761G>A p.Met587Ile missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1939T>C p.Trp647Arg missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1842del p.Pro615LeufsTer13 frameshift_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A number of predicted loss-of-function and damaging missense variants in the SPARCL1 gene, including a de novo LoF variant, were observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). The protein encoded by the SPARCL1 gene, hevin, was shown to induce thalamocortical synapse formation by bridging neurexin 1 -alpha and neuroligin 1-beta following secretion from astrocytes (Singh et al., 2016).

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 number of predicted loss-of-function and damaging missense variants in the SPARCL1 gene, including a de novo LoF variant, were observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). The protein encoded by the SPARCL1 gene, hevin, was shown to induce thalamocortical synapse formation by bridging neurexin 1 -alpha and neuroligin 1-beta following secretion from astrocytes (Singh et al., 2016).

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

Increased from to 3

Description

A number of predicted loss-of-function and damaging missense variants in the SPARCL1 gene, including a de novo LoF variant, were observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). The protein encoded by the SPARCL1 gene, hevin, was shown to induce thalamocortical synapse formation by bridging neurexin 1 -alpha and neuroligin 1-beta following secretion from astrocytes (Singh et al., 2016).

Krishnan Probability Score

Score 0.49414863178969

Ranking 3808/25841 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 1.0714282839756E-6

Ranking 15017/18225 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 0.14809467339895

Ranking 85/18665 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 -0.21784923932557

Ranking 15797/20870 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