Human Gene Module / Chromosome 7 / INTS1

INTS1integrator complex subunit 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
7 / 11
Rare Variants / Common Variants
32 / 0
Aliases
INTS1, INT1,  NET28
Associated Syndromes
-
Chromosome Band
7p22.3
Associated Disorders
ASD, EPS
Relevance to Autism

Krall et al., 2019 reported five individuals, including two sib pairs, with biallelic variants in the INTS1 gene who presented with absent or severely limited speech, abnormal gait, hypotonia, cataracts, and dysmorphic features; three of these individuals were diagnosed with ASD, while a fourth individual presented with autistic features. Oegema et al., 2017 had previously described three unrelated individuals with the same homozygous truncating variant in the INTS1 gene who presented with similar features.

Molecular Function

INTS1 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1) and U2 (RNU2).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to INTS1 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Human mutations in integrator complex subunits link transcriptome integrity to brain development Oegema R , et al. (2017) No Epilepsy/seizures
2 Primary Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies Krall M , et al. (2019) No ASD
3 Support Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland Kurki MI , et al. (2019) No -
4 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
5 Support - Woodbury-Smith M et al. (2022) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Yuan B et al. (2023) Yes -
8 Support - Wang J et al. (2023) Yes -
9 Support - Cirnigliaro M et al. (2023) Yes -
10 Support - M Cecilia Poli et al. () No -
11 Support - Suhua Chang et al. () Yes -
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*150C>T - synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.*109G>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.6255+1G>T - splice_site_variant De novo - - 36881370 Yuan B et al. (2023)
c.575C>T p.Ala192Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4936A>G p.Lys1646Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4970G>A p.Arg1657His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6089C>T p.Ser2030Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6255+1G>T - splice_site_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1188C>T p.Asn396%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5910T>C p.Asn1970%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3921G>A p.Leu1307%3D splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.482del p.Tyr161SerfsTer2 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1361G>T p.Arg454Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6114G>A p.Leu2038= synonymous_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.229C>T p.Arg77Cys missense_variant Familial - Multiplex 30622326 Krall M , et al. (2019)
c.6124del p.Leu2042Ter frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.6491T>C p.Leu2164Pro missense_variant Familial - Simplex 30622326 Krall M , et al. (2019)
c.5494G>A p.Val1832Ile missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.6299G>A p.Arg2100His missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2055C>A p.Ala685%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3010C>T p.Arg1004Trp missense_variant Familial Both parents - 38177409 M Cecilia Poli et al. ()
c.5351C>A p.Ser1784Ter stop_gained Familial Both parents Simplex 28542170 Oegema R , et al. (2017)
c.5290del p.Leu1764CysfsTer16 frameshift_variant Familial - Simplex 30622326 Krall M , et al. (2019)
c.6104_6110del p.Ser2035ThrfsTer6 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.6127_6133del p.Thr2043ProfsTer7 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.5398dup p.Arg1800ProfsTer20 frameshift_variant Familial - Multiplex 30622326 Krall M , et al. (2019)
c.6118_6119insTGG p.Thr2040delinsMetAla inframe_indel De novo - Simplex 39126614 Suhua Chang et al. ()
c.6115_6116del p.Phe2039HisfsTer30 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.3950A>G p.Asp1317Gly missense_variant Familial Both parents Unknown 30679432 Kurki MI , et al. (2019)
c.5621C>T p.Pro1874Leu missense_variant Familial Both parents Multiplex 30622326 Krall M , et al. (2019)
c.3429+7_3429+22del - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.618_619del p.Leu207GlyfsTer3 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Krall et al., 2019 reported five individuals, including two sib pairs, with biallelic variants in the INTS1 gene who presented with absent or severely limited speech, abnormal gait, hypotonia, cataracts, and dysmorphic features; three of these individuals were diagnosed with ASD, while a fourth individual presented with autistic features. Oegema et al., 2017 had previously described three unrelated individuals with the same homozygous truncating variant in the INTS1 gene who presented with similar features.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Krall et al., 2019 reported five individuals, including two sib pairs, with biallelic variants in the INTS1 gene who presented with absent or severely limited speech, abnormal gait, hypotonia, cataracts, and dysmorphic features; three of these individuals were diagnosed with ASD, while a fourth individual presented with autistic features. Oegema et al., 2017 had previously described three unrelated individuals with the same homozygous truncating variant in the INTS1 gene who presented with similar features.

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

Score remained at S

Description

Krall et al., 2019 reported five individuals, including two sib pairs, with biallelic variants in the INTS1 gene who presented with absent or severely limited speech, abnormal gait, hypotonia, cataracts, and dysmorphic features; three of these individuals were diagnosed with ASD, while a fourth individual presented with autistic features. Oegema et al., 2017 had previously described three unrelated individuals with the same homozygous truncating variant in the INTS1 gene who presented with similar features.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
Krishnan Probability Score

Score 0.47761761947416

Ranking 8371/25841 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 0.22412137484881

Ranking 6893/18225 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 0.83241710762936

Ranking 2915/18665 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 0.29702957618895

Ranking 2790/20870 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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