NISCH

protein-coding

nischarin

Gene summary

This gene encodes a nonadrenergic imidazoline-1 receptor protein that localizes to the cytosol and anchors to the inner layer of the plasma membrane. The orthologous mouse protein has been shown to influence cytoskeletal organization and cell migration by binding to alpha-5-beta-1 integrin. In humans, this protein has been shown to bind to the adapter insulin receptor substrate 4 (IRS4) to mediate translocation of alpha-5 integrin from the cell membrane to endosomes. Expression of this protein was reduced in human breast cancers while its overexpression reduced tumor growth and metastasis; possibly by limiting the expression of alpha-5 integrin. In human cardiac tissue, this gene was found to affect cell growth and death while in neural tissue it affected neuronal growth and differentiation. Alternative splicing results in multiple transcript variants encoding differerent isoforms. Some isoforms lack the expected C-terminal domains of a functional imidazoline receptor. [provided by RefSeq, Jan 2013]

MANE transcript

NM_007184.4

Inheritance

—

ClinVar variants

P:1U:226B:21

Top phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr3:52,455,118-52,493,068

External References & Databases

Ensembl (ENSG00000010322)

Transcript & Mutation Effects

hg38 • Region Span ~38.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NISCH variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 214

not providedTotal: 16

Breast-ovarian cancer, familial, susceptibility to, 1Total: 1

Lynch syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007184.4. 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			2 clinvar	7 clinvar	4 clinvar	13
missense			211 clinvar	6 clinvar	4 clinvar	221
nonsense			4 clinvar			4
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	1	0	226	13	8	248

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007184.4	RefSeq	NP_009115.3	21	MANE Select
ENST00000345716.9	Ensembl	ENSP00000339958.4	21	MANE Select
NM_001276293.2	RefSeq	NP_001263222.2	13	Standard
NM_001276294.2	RefSeq	NP_001263223.2	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

glucose metabolic process
apoptotic process
regulation of blood pressure
Rac protein signal transduction
actin cytoskeleton organization

Molecular Function

integrin binding
protein binding
protein kinase binding
phosphatidylinositol binding
identical protein binding

Cellular Component

cytoplasm
early endosome
cytosol
plasma membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000345716
Coding exons: 21
Length: 37954
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125747
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.30	741	939	0.789	0.0000620	9769
Missense (PolyPhen)		182	299.18	0.60833		3126
Synonymous	-0.847	447	425	1.05	0.0000306	3116
Loss of Function	5.95	10	59.5	0.168	0.00000264	707

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension (By similarity). Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons (By similarity). Acts as a modulator of Rac-regulated signal transduction pathways (By similarity). Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity (By similarity). Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation (By similarity). Inhibits also LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation (By similarity). Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells (By similarity). Inhibits lamellipodia formation, when overexpressed (By similarity). Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures. {ECO:0000250, ECO:0000269|PubMed:10882231, ECO:0000269|PubMed:12868002, ECO:0000269|PubMed:15028619, ECO:0000269|PubMed:15028621, ECO:0000269|PubMed:15475348}.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.554
RVIS EVS: -2.31
RVIS percentile EVS: 1.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.901

Gene Damage Prediction

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