ERN1

protein-coding

endoplasmic reticulum to nucleus signaling 1, the group of Endoribonucleases

Gene summary

This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1. [provided by RefSeq, Aug 2017]

MANE transcript

NM_001433.5

Inheritance

—

ClinVar variants

U:126B:9

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr17:64,039,080-64,130,819

External References & Databases

Ensembl (ENSG00000178607)

Transcript & Mutation Effects

hg38 • Region Span ~91.7 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 ERN1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 113

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001433.5. 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			3 clinvar	2 clinvar	1 clinvar	6
missense			116 clinvar	5 clinvar	1 clinvar	122
nonsense			2 clinvar			2
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	0	126	7	2	135

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001433.5	RefSeq	NP_001424.3	22	MANE Select
ENST00000433197.4	Ensembl	ENSP00000401445.2	22	MANE Select
ENST00000606895.2	Ensembl	ENSP00000475519.1	1	Standard
ENST00000680433.1	Ensembl	ENSP00000506094.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Protein processing in endoplasmic reticulum - Homo sapiens (human)
Autophagy - animal - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Apoptosis - Homo sapiens (human)

Biological Process

endothelial cell proliferation
mRNA cleavage
mRNA catabolic process
protein phosphorylation
cell cycle arrest

Molecular Function

magnesium ion binding
endoribonuclease activity
protein kinase activity
protein serine/threonine kinase activity
platelet-derived growth factor receptor binding

Cellular Component

nuclear inner membrane
cytoplasm
mitochondrion
endoplasmic reticulum
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000433197
Coding exons: 22
Length: 91678
Individuals with no LoFs: 124647
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 124658
p: 0.0000441

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.27	413	565	0.732	0.0000339	6326
Missense (PolyPhen)		98	184.63	0.53078		2124
Synonymous	0.254	236	241	0.979	0.0000161	1925
Loss of Function	5.44	8	49.2	0.163	0.00000268	574

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000075	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR) (PubMed:11779464, PubMed:11175748, PubMed:12637535, PubMed:9637683, PubMed:21317875). In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP (PubMed:21317875). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity (PubMed:21317875). The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA (PubMed:11779464, PubMed:24508390, PubMed:21317875). The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes (PubMed:11779464, PubMed:24508390, PubMed:21317875). {ECO:0000269|PubMed:11175748, ECO:0000269|PubMed:11779464, ECO:0000269|PubMed:12637535, ECO:0000269|PubMed:21317875, ECO:0000269|PubMed:9637683, ECO:0000305|PubMed:24508390}.;

Recessive Scores

pRec: 0.311

Intolerance Scores

RVIS EVS: -0.44
RVIS percentile EVS: 24.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.988

Gene Damage Prediction

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