Human Gene Module / Chromosome 13 / INTS6

INTS6Integrator complex subunit 6

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
23 / 0
Aliases
INTS6, DBI-1,  DDX26,  DDX26A,  DICE1,  HDB,  INT6,  Notchl2
Associated Syndromes
-
Chromosome Band
13q14.3
Associated Disorders
-
Relevance to Autism

Two de novo variants (one nonsense, one missense) in the INTS6 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015). Peng et al., 2025 reported a cohort of 23 families harboring monoalleleic likely gene-disruptive or de novo missense variants in the INTS6 gene presenting with a neurodevelopmental disorder characterized by speech-language problems (90.9%), autism spectrum disorder (77.3%), motor delay (72.2%), intellectual disability (72.2%), and sleep disturbance (62.5%); in the same report, behavioral assessment of a nervous-system conditional knockout mouse model demonstrated that Ints6 cKO heterozygous mice displayed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants.

Molecular Function

The protein encoded by this gene is a DEAD box protein that is part of a complex that interacts with the C-terminus of RNA polymerase II and is involved in 3' end processing of snRNAs.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser
Reports related to INTS6 (7 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 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) No -
3 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
4 Recent Recommendation Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
7 Recent Recommendation - Xiaoxia Peng et al. (2025) Yes ADHD, epilepsy/seizures
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.553C>T p.Gln185Ter stop_gained De novo - Simplex 40966112 Qing Su et al. (2025)
c.976A>T p.Lys326Ter stop_gained De novo - Simplex 40966112 Qing Su et al. (2025)
c.613+3_613+6del p.? splice_site_variant De novo - - 40966112 Qing Su et al. (2025)
c.1224G>A p.Trp408Ter stop_gained De novo - Simplex 40966112 Qing Su et al. (2025)
c.1828C>T p.Arg610Ter stop_gained De novo - Simplex 40966112 Qing Su et al. (2025)
c.2210C>A p.Ser737Ter stop_gained Unknown - Unknown 40966112 Qing Su et al. (2025)
c.1607T>A p.Leu536Ter stop_gained De novo - Multiplex 40966112 Qing Su et al. (2025)
c.616C>T p.Arg206Cys missense_variant De novo - Simplex 40966112 Qing Su et al. (2025)
c.682C>G p.Gln228Glu missense_variant De novo - Simplex 40966112 Qing Su et al. (2025)
c.850C>T p.Pro284Ser missense_variant De novo - Simplex 40966112 Qing Su et al. (2025)
c.574+3_574+6del - splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1828C>T p.Arg610Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.613+2T>C p.? splice_site_variant Unknown Not paternal - 40966112 Qing Su et al. (2025)
c.332A>G p.Tyr111Cys missense_variant De novo - Multiplex 40966112 Qing Su et al. (2025)
c.1199A>G p.His400Arg missense_variant De novo - Multiplex 40966112 Qing Su et al. (2025)
c.410C>T p.Thr137Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2104+1_2104+8delinsTC p.? splice_site_variant De novo - Unknown 40966112 Qing Su et al. (2025)
c.102_103del p.Phe35HisfsTer41 frameshift_variant De novo - Simplex 40966112 Qing Su et al. (2025)
c.1803_1804delAA p.Glu603ThrfsTer2 frameshift_variant De novo - Simplex 40966112 Qing Su et al. (2025)
c.828_829del p.Val278SerfsTer37 frameshift_variant Unknown Not maternal - 40966112 Qing Su et al. (2025)
c.272C>T p.Ser91Phe missense_variant De novo - Multiplex (monozygotic twins) 40966112 Qing Su et al. (2025)
c.1433delinsGT p.Val478GlyfsTer21 frameshift_variant Familial Maternal Simplex 40966112 Qing Su et al. (2025)
c.1190A>C p.Gln397Pro missense_variant De novo (germline mosaicism) - Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants (one nonsense, one missense) in the INTS6 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value < 0.05), and no rare effect types were reported in the Exome Variant Server. This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

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
2
icon
2

Score remained at 2

New Scoring Scheme
Description

Two de novo variants (one nonsense, one missense) in the INTS6 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value < 0.05), and no rare effect types were reported in the Exome Variant Server. This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015).

Reports Added
[New Scoring Scheme]
1/1/2016
2
icon
2

Score remained at 2

Description

Two de novo variants (one nonsense, one missense) in the INTS6 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Excess of rare, inherited truncating mutations in autism.2015] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
10/1/2015
3
icon
2

Decreased from 3 to 2

Description

Two de novo variants (one nonsense, one missense) in the INTS6 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server. This gene was recently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

7/1/2015
icon
3

Increased from to 3

Description

Two de novo variants (one nonsense, one missense) in the INTS6 gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014. Krumm et al., 2015 reported that no de novo SNVs in this gene were observed in SSC unaffected siblings (de novo SNV P-value <0.05), and no rare effect types were reported in the Exome Variant Server.

Krishnan Probability Score

Score 0.4885389226411

Ranking 6719/25841 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 0.99999653473509

Ranking 376/18225 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 0.896

Ranking 147/239 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 0.065481930641939

Ranking 52/18665 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 0.24088232172334

Ranking 3607/20870 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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