Human Gene Module / Chromosome 11 / TSPAN4

TSPAN4tetraspanin 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
4 / 0
Aliases
TSPAN4, NAG-2,  NAG2,  TETRASPAN,  TM4SF7,  TSPAN-4
Associated Syndromes
-
Chromosome Band
11p15.5
Associated Disorders
-
Relevance to Autism

Two de novo variants (one frameshift variant, one missense variant) were observed in the TSPAN4 gene in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014, while a paternally-transmitted frameshift variant in this gene was observed in two of three affected siblings from a multiplex family from the iHART cohort in Ruzzo et al., 2019. Two separate studies used TADA analysis to identify TSPAN4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Molecular Function

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein and is similar in sequence to its family member CD53 antigen. It is known to complex with integrins and other transmembrane 4 superfamily proteins.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TSPAN4 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Recent Recommendation Nonrandom occurrence of multiple de novo coding variants in a proband indicates the existence of an oligogenic model in autism Du Y , et al. (2019) Yes -
3 Recent Recommendation Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) 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 - Kuokuo Li et al. (2024) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.563C>T p.Ala188Val missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.128C>T p.Thr43Met missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.702del p.Asp234GlufsTer168 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.429del p.Asp144ThrfsTer51 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants (one frameshift variant, one missense variant) were observed in the TSPAN4 gene in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014, while a paternally-transmitted frameshift variant in this gene was observed in two of three affected siblings from a multiplex family from the iHART cohort in Ruzzo et al., 2019. Two separate studies used TADA analysis to identify TSPAN4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

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

Two de novo variants (one frameshift variant, one missense variant) were observed in the TSPAN4 gene in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014, while a paternally-transmitted frameshift variant in this gene was observed in two of three affected siblings from a multiplex family from the iHART cohort in Ruzzo et al., 2019. Two separate studies used TADA analysis to identify TSPAN4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo variants (one frameshift variant, one missense variant) were observed in the TSPAN4 gene in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014, while a paternally-transmitted frameshift variant in this gene was observed in two of three affected siblings from a multiplex family from the iHART cohort in Ruzzo et al., 2019. Two separate studies used TADA analysis to identify TSPAN4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
4

Increased from to 4

Description

Two de novo variants (one frameshift variant, one missense variant) were observed in the TSPAN4 gene in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014, while a paternally-transmitted frameshift variant in this gene was observed in two of three affected siblings from a multiplex family from the iHART cohort in Ruzzo et al., 2019. Two separate studies used TADA analysis to identify TSPAN4 as an ASD candidate gene with a q-value < 0.1 (Du et al., 2019; Ruzzo et al., 2019).

Krishnan Probability Score

Score 0.32604774815664

Ranking 25313/25841 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 2.5243425121187E-6

Ranking 14719/18225 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 0.11263207808204

Ranking 70/18665 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 -0.48299705013287

Ranking 19109/20870 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