EIF2AK3

protein-coding

eukaryotic translation initiation factor 2 alpha kinase 3, the group of Eukaryotic translation initiation factor 2 alpha kinases

Gene summary

The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Sep 2015]

MANE transcript

NM_004836.7

Inheritance

ClinVar variants

P:114U:370B:317

Top phenotype

Epiphyseal dysplasia, multiple, with early-onset diabetes mellitus (Wolcott-Rallison syndrome)

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr2:88,556,741-88,691,518

External References & Databases

Ensembl (ENSG00000172071)

Transcript & Mutation Effects

hg38 • Region Span ~134.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wolcott-Rallison syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: G2P

Wolcott-Rallison syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: Orphanet

Wolcott-Rallison syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: Labcorp Genetics (formerly Invitae)

Wolcott-Rallison syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: Ambry Genetics

Wolcott-Rallison syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: PanelApp Australia

Wolcott-Rallison syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: Natera

Wolcott-Rallison syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009192

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Epiphyseal dysplasia, multiple, with early-onset diabetes mellitus (Wolcott-Rallison syndrome)AR

Manifestation: Cardiovascular; Dental; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Endocrine

Rationale: Individuals can have infantile-onset insulin-dependent diabetes mellitus (and may present with severe sequelae of diabetes, which may lead to death) prior to obvious manifestation of other, recognizable features, and prompt recognition and treatment could decrease morbidity and mortality, though treatment can be challenging

Refs: 5008828; 7094931; 7551159; 9598721; 10932183; 12960215; 16813601; 21050479; 21648287; 21518408; 22672868; 23759358

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2AK3 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 801

Wolcott-Rallison dysplasiaTotal: 242

Inborn genetic diseasesTotal: 120

not specifiedTotal: 36

EIF2AK3-related disorderTotal: 20

Connective tissue disorderTotal: 11

Monogenic diabetesTotal: 9

Syndromic Monogenic DiabetesTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004836.7. 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			7 clinvar	298 clinvar		305
missense		5 clinvar	354 clinvar	17 clinvar	1 clinvar	377
nonsense	21 clinvar	15 clinvar	1 clinvar			37
start loss		1 clinvar				1
frameshift	25 clinvar	26 clinvar	4 clinvar			55
splice donor/acceptor (+/-2bp)	1 clinvar	20 clinvar	4 clinvar	1 clinvar		26
Total	47	67	370	316	1	801

Highest pathogenic variant AF is 0.0000074350733

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004836.7	RefSeq	NP_004827.4	17	MANE Select
ENST00000303236.9	Ensembl	ENSP00000307235.3	17	MANE Select
NM_001313915.2	RefSeq	NP_001300844.1	15	Standard
ENST00000652099.1	Ensembl	ENSP00000498211.1	4	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)
Influenza A - Homo sapiens (human)
Protein processing in endoplasmic reticulum - Homo sapiens (human)
Autophagy - animal - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)

Biological Process

skeletal system development
ossification
angiogenesis
chondrocyte development
protein phosphorylation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
eukaryotic translation initiation factor 2alpha kinase activity
protein binding
ATP binding

Cellular Component

cytoplasm
endoplasmic reticulum
endoplasmic reticulum membrane
membrane
cytosolic ribosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303236
Coding exons: 17
Length: 70836
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125748
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.03	438	575	0.761	0.0000293	7305
Missense (PolyPhen)		69	154.52	0.44654		1927
Synonymous	0.162	203	206	0.986	0.0000107	2140
Loss of Function	4.75	15	51.9	0.289	0.00000288	631

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' during the unfolded protein response (UPR) and in response to low amino acid availability. Converts phosphorylated eIF-2-alpha/EIF2S1 either in a global protein synthesis inhibitor, leading to a reduced overall utilization of amino acids, or to a translation initiation activator of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Serves as a critical effector of unfolded protein response (UPR)- induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function. {ECO:0000250|UniProtKB:Q9Z2B5}.;
Disease: DISEASE: Wolcott-Rallison syndrome (WRS) [MIM:226980]: A rare autosomal recessive disorder, characterized by permanent neonatal or early infancy insulin-dependent diabetes and, at a later age, epiphyseal dysplasia, osteoporosis, growth retardation and other multisystem manifestations, such as hepatic and renal dysfunctions, mental retardation and cardiovascular abnormalities. {ECO:0000269|PubMed:10932183}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.587

Intolerance Scores

LoFtool: 0.657
RVIS EVS: 0.09
RVIS percentile EVS: 60.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.682

Gene Damage Prediction

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