ITSN1

protein-coding

intersectin 1, the group of EF-hand domain containing|C2 domain containing|Dbl family Rho GEFs|Pleckstrin homology domain containing

Gene summary

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. This protein has been shown to interact with dynamin, CDC42, SNAP23, SNAP25, SPIN90, EPS15, EPN1, EPN2, and STN2. Multiple transcript variants encoding different isoforms have been found for this gene, but the full-length nature of only two of them have been characterized so far. [provided by RefSeq, Jul 2008]

Previous symbols:

SH3D1A
ITSN

MANE transcript

NM_003024.3

Inheritance

AR, AD

ClinVar variants

P:31U:349B:58

Top phenotype

nephrotic syndrome

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr21:33,642,400-33,899,861

External References & Databases

Ensembl (ENSG00000205726)

Transcript & Mutation Effects

hg38 • Region Span ~257.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0005377

Submitter: PanelApp Australia

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published (AR scope): No scorable published cases of biallelic (autosomal recessive) ITSN1 variants causing neurodevelopmental disorder were identified in the current literature review. Available published human data primarily describe heterozygous (autosomal dominant) de novo variants, which are outside the scope of this AR GDR. Case-level = 0; segregation = 0; case-control = 0 Published (AD context; not scored for AR): PMID: 34709922 – Reports individuals with de novo heterozygous ITSN1 variants associated with neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, and epilepsy. As these represent monoallelic/dominant cases, they are not scorable under the autosomal recessive framework. Case-level = 0 (AR scope); segregation = 0; case-control = 0 PMID: 28773821 – Large neurodevelopmental cohort identifying de novo heterozygous variants in ITSN1 in individuals with developmental delay and autism spectrum disorder; not applicable to AR scoring. Case-level = 0 (AR scope); segregation = 0; case-control = 0 AD-context evidence total (not scored for AR) = 0 Provisional classification Limited evidence for ITSN1-related autosomal recessive neurodevelopmental disorder. No published biallelic cases are currently available; the only genetic evidence derives from one unpublished consanguineous family with a homozygous predicted loss-of-function variant. Experimental support is limited to biological plausibility derived from autosomal dominant neurodevelopmental studies. Published genetic evidence total = 0/12 Genetic evidence – Our cases: Family 1 –one proband. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation = 0; case-control = 0; Family 1 total = 1.0 Our cases total = 1.0/12 Total genetic evidence (published AR + our cases) 1.0/12 Experimental evidence – Published: PMID: 34709922; PMID: 28773821 – De novo heterozygous ITSN1 variants have been reported in individuals with autism spectrum disorder, intellectual disability, and epilepsy, supporting involvement of ITSN1 in neurodevelopment. Functional studies demonstrate that ITSN1 encodes a neuronal scaffold protein involved in synaptic vesicle endocytosis and neuronal signaling, and mouse models show neurobehavioral abnormalities when ITSN1 is disrupted. Although these findings relate primarily to autosomal dominant effects, they provide biological plausibility that disruption of ITSN1 impacts neurodevelopment. Function consistent with disease = 0.5 Experimental evidence total = 0.5/6 Overall score Genetic evidence = 1.0 Experimental evidence = 0.5 Overall score = 1.5

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITSN1 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 193

Inborn genetic diseasesTotal: 191

ITSN1-related disorderTotal: 69

Autistic behaviorTotal: 9

Neurodevelopmental disorderTotal: 6

not specifiedTotal: 5

ITSN1-related neurodevelopmental disordersTotal: 2

AutismTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003024.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	31 clinvar	4 clinvar	36
missense		1 clinvar	304 clinvar	22 clinvar	1 clinvar	328
nonsense	12 clinvar	5 clinvar	16 clinvar			33
start loss						0
frameshift	6 clinvar	3 clinvar	15 clinvar			24
splice donor/acceptor (+/-2bp)		4 clinvar	13 clinvar			17
Total	18	13	349	53	5	438

Highest pathogenic variant AF is 0.00006439426

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003024.3	RefSeq	NP_003015.2	39	MANE Select
ENST00000381318.8	Ensembl	ENSP00000370719.3	39	MANE Select
NM_001001132.2	RefSeq	NP_001001132.1	29	Standard
NM_001331008.2	RefSeq	NP_001317937.1	27	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
Signaling by GPCR
Signal Transduction
Vesicle-mediated transport
Membrane Trafficking

Biological Process

G protein-coupled receptor signaling pathway
small GTPase mediated signal transduction
viral process
positive regulation of kinase activity
regulation of Rho protein signal transduction

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
calcium ion binding
protein binding
kinase activator activity

Cellular Component

cytosol
plasma membrane
clathrin-coated pit
lamellipodium
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381318
Coding exons: 39
Length: 257460
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.61	644	959	0.672	0.0000542	11253
Missense (PolyPhen)		136	276.57	0.49173		3302
Synonymous	0.341	356	364	0.977	0.0000218	3263
Loss of Function	8.30	16	110	0.146	0.00000600	1195

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as guanine nucleotide exchange factor (GEF) specific for the CDC42 GTPase (By similarity). Adapter protein that may provide indirect link between the endocytic membrane traffic and the actin assembly machinery. May regulate the formation of clathrin-coated vesicles. Involved in endocytosis of integrin beta-1 (ITGB1) and transferrin receptor (TFR); internalization of ITGB1 as DAB2-dependent cargo but not TFR may involve association with DAB2. Isoform 1 could be involved in brain-specific synaptic vesicle recycling. Inhibits ARHGAP31 activity toward RAC1. {ECO:0000250, ECO:0000269|PubMed:11744688, ECO:0000269|PubMed:22648170}.;

Recessive Scores

pRec: 0.202

Intolerance Scores

LoFtool: 0.512
RVIS EVS: -2.01
RVIS percentile EVS: 1.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.871

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium