EIF2AK3

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

Basic information

Region (hg38): 2:88556740-88691518

Links

ENSG00000172071 ∙ NCBI:9451 ∙ OMIM:604032 ∙ HGNC:3255 ∙ Uniprot:Q9NZJ5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Wolcott-Rallison syndrome (Definitive), mode of inheritance: AR
• Wolcott-Rallison syndrome (Strong), mode of inheritance: AR
• Wolcott-Rallison syndrome (Definitive), mode of inheritance: AR
• Wolcott-Rallison syndrome (Strong), mode of inheritance: AR
• Wolcott-Rallison syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epiphyseal dysplasia, multiple, with early-onset diabetes mellitus (Wolcott-Rallison syndrome)	AR	Endocrine	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	Cardiovascular; Dental; Dermatologic; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Renal	5008828; 7094931; 7551159; 9598721; 10932183; 12960215; 16813601; 21050479; 21648287; 21518408; 22672868; 23759358

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EIF2AK3 gene.

• not provided (498 variants)
• Wolcott-Rallison dysplasia (151 variants)
• Inborn genetic diseases (33 variants)
• not specified (23 variants)
• Connective tissue disorder (12 variants)
• Monogenic diabetes (9 variants)
• EIF2AK3-related condition (1 variants)
• Menkes kinky-hair syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EIF2AK3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	118	2	126
missense		2	233	8	4	247
nonsense	15	4	1			20
start loss						0
frameshift	18	6	1			25
inframe indel			8		1	9
splice donor/acceptor (+/-2bp)	1	13	1			15
splice region			9	16	1	26
non coding			28	55	20	103
Total	34	25	278	181	27

Highest pathogenic variant AF is 0.00000658

Variants in EIF2AK3

This is a list of pathogenic ClinVar variants found in the EIF2AK3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-88556834-GGATT-G		Wolcott-Rallison dysplasia	Uncertain significance (Jun 14, 2016)
2-88556860-AAAACAT-A		Wolcott-Rallison dysplasia	Uncertain significance (Jun 14, 2016)
2-88557024-G-A		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557101-C-T		Wolcott-Rallison dysplasia	Uncertain significance (Jan 12, 2018)
2-88557277-C-A		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557328-A-C		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557371-CAG-C		Wolcott-Rallison dysplasia	Uncertain significance (Jun 14, 2016)
2-88557376-G-A		Wolcott-Rallison dysplasia	Uncertain significance (Jun 14, 2016)
2-88557380-T-C		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557396-T-C		Wolcott-Rallison dysplasia	Uncertain significance (Jan 15, 2018)
2-88557424-C-CTA		Wolcott-Rallison dysplasia	Uncertain significance (Jun 14, 2016)
2-88557450-C-G		Wolcott-Rallison dysplasia	Uncertain significance (Jun 14, 2016)
2-88557465-A-C		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557561-T-A		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557632-T-G		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557637-G-A		Wolcott-Rallison dysplasia	Uncertain significance (Jan 13, 2018)
2-88557748-C-T			Likely benign (Dec 31, 2022)
2-88557750-A-G			Likely benign (Jul 18, 2018)
2-88557757-A-G			Likely benign (Aug 17, 2023)
2-88557757-A-T			Uncertain significance (Jan 12, 2022)
2-88557763-G-A			Likely benign (Jan 18, 2024)
2-88557768-T-TG			Uncertain significance (Oct 13, 2023)
2-88557770-G-A			Uncertain significance (Aug 03, 2021)
2-88557793-C-T			Likely benign (Dec 11, 2023)
2-88557794-G-T		Wolcott-Rallison dysplasia	Uncertain significance (Apr 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EIF2AK3	protein_coding	protein_coding	ENST00000303236	17	70836

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00276	0.997	125715	0	33	125748	0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.03	438	575	0.761	0.0000293	7305
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000304	0.000304
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000109	0.000109
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.000168	0.000167
Middle Eastern	0.000109	0.000109
South Asian	0.0000981	0.0000980
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Mitophagy - animal - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Measles - Homo sapiens (human);Apoptosis - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Translation Factors;Alzheimers Disease;Photodynamic therapy-induced unfolded protein response;VEGFA-VEGFR2 Signaling Pathway;PERK regulates gene expression;Unfolded Protein Response (UPR);Metabolism of proteins;regulation of eif2 (Consensus)

Recessive Scores

• pRec: 0.587

Intolerance Scores

• loftool: 0.657
• rvis_EVS: 0.09
• rvis_percentile_EVS: 60.65

Haploinsufficiency Scores

• pHI: 0.261
• hipred: Y
• hipred_score: 0.698
• ghis: 0.519

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.682

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Eif2ak3
• Phenotype: immune system phenotype; skeleton phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); neoplasm; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: skeletal system development;ossification;angiogenesis;chondrocyte development;protein phosphorylation;activation of cysteine-type endopeptidase activity involved in apoptotic process;ER overload response;endoplasmic reticulum organization;positive regulation of vascular endothelial growth factor production;positive regulation of gene expression;regulation of translational initiation by eIF2 alpha phosphorylation;negative regulation of translation;peptidyl-serine phosphorylation;calcium-mediated signaling;bone mineralization;endoplasmic reticulum unfolded protein response;endocrine pancreas development;negative regulation of myelination;negative regulation of translational initiation in response to stress;cellular response to amino acid starvation;response to endoplasmic reticulum stress;eiF2alpha phosphorylation in response to endoplasmic reticulum stress;PERK-mediated unfolded protein response;cellular response to glucose starvation;positive regulation of transcription by RNA polymerase I;protein autophosphorylation;insulin-like growth factor receptor signaling pathway;protein homooligomerization;regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation;cellular response to cold;positive regulation of protein localization to nucleus;regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway;response to manganese-induced endoplasmic reticulum stress
• Cellular component: cytoplasm;endoplasmic reticulum;endoplasmic reticulum membrane;membrane;cytosolic ribosome;integral component of endoplasmic reticulum membrane;perinuclear region of cytoplasm
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;eukaryotic translation initiation factor 2alpha kinase activity;protein binding;ATP binding;enzyme binding;protein phosphatase binding;identical protein binding;protein homodimerization activity;Hsp90 protein binding