Human Gene Module / Chromosome 15 / THBS1

THBS1Thrombospondin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
8 / 2
Aliases
THBS1, TSP,  THBS,  TSP1,  TSP-1,  THBS-1
Associated Syndromes
-
Chromosome Band
15q14
Associated Disorders
-
Relevance to Autism

Sanger sequencing of 313 ASD cases and 350 controls (both of Han Chinese descent) identified five common variants, including one common variant (c.1567A>G; p.T523A) associated with autism, and seven rare variants, two of which (c.2429G>A; p.R810Q, c.3496G>C; p.E1166Q) were absent in controls and dbSNP (Lu et al., 2014). Combined association analysis of THBS1 rare variants (MAF<0.01) in patients and Asian samples in the 1000 Genomes project revealed association between these rare variants and autism (P=0.039). Characterization of thrombospondin 1 knockout mice in Leana-Sandoval et al., 2025 found that these mice displayed decreased perineuronal net density and strengthened synaptic transmission in hippocampal field CA2, severely disrupted social interactions, and emotional alterations.

Molecular Function

Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.

External Links
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Human
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SFARI Genomic Platforms
GPF browser
Reports related to THBS1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Common and rare variants of the THBS1 gene associated with the risk for autism Lu L , et al. (2014) Yes -
2 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
3 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Gerardo Leana-Sandoval et al. (2025) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.294G>T p.Lys98Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2875C>T p.Arg959Ter stop_gained De novo - - 31452935 Feliciano P et al. (2019)
c.2875C>T p.Arg959Ter stop_gained De novo - Multiplex 30504930 Guo H , et al. (2018)
c.2429G>A p.Arg810Gln missense_variant Unknown - Unknown 25304225 Lu L , et al. (2014)
c.2876G>A p.Arg959Gln missense_variant Unknown - Unknown 25304225 Lu L , et al. (2014)
c.3251G>A p.Gly1084Glu missense_variant Unknown - Unknown 25304225 Lu L , et al. (2014)
c.3496G>C p.Glu1166Gln missense_variant Unknown - Unknown 25304225 Lu L , et al. (2014)
c.2749G>T p.Asp917Tyr missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1290G>A p.(=) synonymous_variant - - - 25304225 Lu L , et al. (2014)
c.1567A>G p.Thr523Ala missense_variant - - - 25304225 Lu L , et al. (2014)
SFARI Gene score
2

Strong Candidate

Sanger sequencing of 313 ASD cases and 350 controls (both of Han Chinese descent) identified five common variants, including one common variant (c.1567A>G; p.T523A) associated with autism, and seven rare variants, two of which (c.2429G>A; p.R810Q, c.3496G>C; p.E1166Q) were absent in controls and dbSNP (Lu et al., 2014). Combined association analysis of THBS1 rare variants (MAF < 0.01) in patients and Asian samples in the 1000 Genomes project revealed association between these rare variants and autism (P=0.039). A de novo postzygotic mosaic missense variant (Allele Fraction 0.2) in the THBS1 gene was identified in a male ASD proband in Lim et al., 2017.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Sanger sequencing of 313 ASD cases and 350 controls (both of Han Chinese descent) identified five common variants, including one common variant (c.1567A>G; p.T523A) associated with autism, and seven rare variants, two of which (c.2429G>A; p.R810Q, c.3496G>C; p.E1166Q) were absent in controls and dbSNP (Lu et al., 2014). Combined association analysis of THBS1 rare variants (MAF < 0.01) in patients and Asian samples in the 1000 Genomes project revealed association between these rare variants and autism (P=0.039). A de novo postzygotic mosaic missense variant (Allele Fraction 0.2) in the THBS1 gene was identified in a male ASD proband in Lim et al., 2017.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Sanger sequencing of 313 ASD cases and 350 controls (both of Han Chinese descent) identified five common variants, including one common variant (c.1567A>G; p.T523A) associated with autism, and seven rare variants, two of which (c.2429G>A; p.R810Q, c.3496G>C; p.E1166Q) were absent in controls and dbSNP (Lu et al., 2014). Combined association analysis of THBS1 rare variants (MAF < 0.01) in patients and Asian samples in the 1000 Genomes project revealed association between these rare variants and autism (P=0.039). A de novo postzygotic mosaic missense variant (Allele Fraction 0.2) in the THBS1 gene was identified in a male ASD proband in Lim et al., 2017.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Sanger sequencing of 313 ASD cases and 350 controls (both of Han Chinese descent) identified five common variants, including one common variant (c.1567A>G; p.T523A) associated with autism, and seven rare variants, two of which (c.2429G>A; p.R810Q, c.3496G>C; p.E1166Q) were absent in controls and dbSNP (Lu et al., 2014). Combined association analysis of THBS1 rare variants (MAF < 0.01) in patients and Asian samples in the 1000 Genomes project revealed association between these rare variants and autism (P=0.039). A de novo postzygotic mosaic missense variant (Allele Fraction 0.2) in the THBS1 gene was identified in a male ASD proband in Lim et al., 2017.

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
icon
4

Increased from to 4

Description

Sanger sequencing of 313 ASD cases and 350 controls (both of Han Chinese descent) identified five common variants, including one common variant (c.1567A>G; p.T523A) associated with autism, and seven rare variants, two of which (c.2429G>A; p.R810Q, c.3496G>C; p.E1166Q) were absent in controls and dbSNP (Lu et al., 2014). Combined association analysis of THBS1 rare variants (MAF < 0.01) in patients and Asian samples in the 1000 Genomes project revealed association between these rare variants and autism (P=0.039). A de novo postzygotic mosaic missense variant (Allele Fraction 0.2) in the THBS1 gene was identified in a male ASD proband in Lim et al., 2017.

Krishnan Probability Score

Score 0.41281400333065

Ranking 21993/25841 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 0.99907312729083

Ranking 1054/18225 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 0.77392941786676

Ranking 1822/18665 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 8

Ranking 237/461 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 0.116742002924

Ranking 5787/20870 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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