Human Gene Module / Chromosome 15 / THBS1

THBS1Thrombospondin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
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).

Molecular Function

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

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to THBS1 (5 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 -
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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