Human Gene Module / Chromosome 21 / ITSN1

ITSN1intersectin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
18 / 0
Aliases
ITSN1, ITSN,  SH3D1A,  SH3P17
Associated Syndromes
-
Chromosome Band
21q22.11
Associated Disorders
-
Relevance to Autism

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

Molecular Function

The protein encoded by this gene is a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly machinery. In addition, the encoded protein may regulate the formation of clathrin-coated vesicles and could be involved in synaptic vesicle recycling.

SFARI Genomic Platforms
Reports related to ITSN1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Recent Recommendation Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Recent Recommendation - Bruel AL et al. (2021) Yes ADHD, epilepsy/seizures
6 Support - Mosallaei M et al. (2022) No Autistic features
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1258G>T p.Glu420Ter stop_gained Unknown - - 34707297 Bruel AL et al. (2021)
c.789-2A>G - splice_site_variant De novo NA - 34707297 Bruel AL et al. (2021)
c.1960C>T p.Gln654Ter stop_gained De novo NA - 34707297 Bruel AL et al. (2021)
- p.Gln711Ter stop_gained Familial Paternal - 31452935 Feliciano P et al. (2019)
c.2894dup p.Tyr965Ter frameshift_variant Unknown - - 34707297 Bruel AL et al. (2021)
c.4354A>T p.Asn1452Tyr missense_variant De novo NA - 34707297 Bruel AL et al. (2021)
c.1726G>T p.Glu576Ter stop_gained Familial Paternal - 34707297 Bruel AL et al. (2021)
- p.Pro156fs frameshift_variant Familial Paternal - 31452935 Feliciano P et al. (2019)
c.1130G>A p.Arg377His missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.4841C>T p.Pro1614Leu missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.5099T>G p.Leu1700Arg missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.1952+1del - splice_site_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1726G>T p.Glu576Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1389_1392del p.Lys463AsnfsTer5 frameshift_variant Unknown - - 34707297 Bruel AL et al. (2021)
c.3116G>A p.Trp1039Ter stop_gained Familial Paternal Multiplex 34707297 Bruel AL et al. (2021)
c.186-2A>G - splice_site_variant Familial Both parents Multiplex 35174982 Mosallaei M et al. (2022)
c.2842_2843del p.Met948ValfsTer41 frameshift_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.490_491del p.Pro164CysfsTer22 frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

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
2

Initial score established: 2

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

10/1/2021
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

7/1/2021
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

4/1/2021
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

1/1/2021
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

10/1/2020
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

7/1/2020
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

4/1/2020
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

1/1/2020
3

Initial score established: 3

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

10/1/2019
3

Initial score established: 3

New Scoring Scheme
Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.52134155925362

Ranking 1679/25841 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.
ExAC Score

Score 0.99999997363569

Ranking 159/18225 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
Sanders TADA Score

Score 0.78582221879538

Ranking 1983/18665 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).
Zhang D Score

Score -0.22445506295386

Ranking 15907/20870 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.
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