EIF2AK4

eukaryotic translation initiation factor 2 alpha kinase 4, the group of Eukaryotic translation initiation factor 2 alpha kinases

Basic information

Region (hg38): 15:39934115-40035591

Links

ENSG00000128829 ∙ NCBI:440275 ∙ OMIM:609280 ∙ HGNC:19687 ∙ Uniprot:Q9P2K8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pulmonary venoocclusive disease (Supportive), mode of inheritance: AR
• pulmonary venoocclusive disease 2 (Supportive), mode of inheritance: AD
• heritable pulmonary arterial hypertension (Supportive), mode of inheritance: AD
• pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (Definitive), mode of inheritance: AR
• pulmonary venoocclusive disease 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pulmonary venoocclusive disease 2	AR	Cardiovascular; Pulmonary	Medical treatment (eg, with calcium antagonists, anticoagulants, prostanoids, endothelin receptor antagonists, etc.) may be beneficial, though lung transplantation may be required	Cardiovascular; Pulmonary	24292273

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EIF2AK4 gene.

• not provided (20 variants)
• Familial pulmonary capillary hemangiomatosis (10 variants)
• EIF2AK4-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EIF2AK4 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				36	5	41
missense			81	17	6	104
nonsense	9	2				11
start loss						0
frameshift	13	4	1			18
inframe indel					1	1
splice donor/acceptor (+/-2bp)	1					1
splice region			4	6	5	15
non coding			3	33	123	159
Total	23	6	85	86	135

Highest pathogenic variant AF is 0.0000526

Variants in EIF2AK4

This is a list of pathogenic ClinVar variants found in the EIF2AK4 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-39934184-C-A		Familial pulmonary capillary hemangiomatosis	Benign (Sep 13, 2021)
15-39934206-G-C			Uncertain significance (Nov 14, 2021)
15-39934236-A-C		Inborn genetic diseases	Uncertain significance (Jul 09, 2021)
15-39934242-C-T		Inborn genetic diseases	Uncertain significance (Jan 30, 2024)
15-39934243-G-A		EIF2AK4-related disorder	Likely benign (Jun 24, 2021)
15-39934254-C-G			Uncertain significance (Jan 23, 2024)
15-39934255-G-A			Likely benign (May 08, 2018)
15-39934270-C-T			Likely benign (May 15, 2018)
15-39934277-C-T		Familial pulmonary capillary hemangiomatosis	Likely pathogenic (Sep 07, 2019)
15-39934282-C-T			Likely benign (Oct 25, 2022)
15-39934294-T-C		not specified • Familial pulmonary capillary hemangiomatosis	Benign (Feb 01, 2024)
15-39934297-C-T			Likely benign (Apr 13, 2022)
15-39934301-G-T		Inborn genetic diseases	Uncertain significance (Oct 06, 2022)
15-39934310-C-G		Inborn genetic diseases	Uncertain significance (Nov 17, 2023)
15-39934320-G-A		Inborn genetic diseases	Uncertain significance (Sep 01, 2021)
15-39934335-G-T		Inborn genetic diseases	Uncertain significance (Apr 22, 2024)
15-39939299-A-G			Benign (Jun 14, 2018)
15-39939424-A-T			Benign (Jun 14, 2018)
15-39939503-A-G		Familial pulmonary capillary hemangiomatosis	Pathogenic (-)
15-39939508-A-G		Inborn genetic diseases	Uncertain significance (Mar 31, 2024)
15-39939532-G-C		Inborn genetic diseases	Uncertain significance (Feb 13, 2024)
15-39939578-T-C		Inborn genetic diseases	Uncertain significance (May 25, 2022)
15-39939579-G-A			Likely benign (Oct 06, 2021)
15-39939621-A-C		Familial pulmonary capillary hemangiomatosis	Likely pathogenic (-)
15-39939800-C-A			Benign (Jun 14, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EIF2AK4	protein_coding	protein_coding	ENST00000263791	39	101451

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.24e-15	1.00	125005	0	180	125185	0.000719

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.67	680	906	0.751	0.0000496	10800
Missense in Polyphen		168	281.75	0.59627		3413
Synonymous	0.500	335	347	0.966	0.0000198	3108
Loss of Function	5.04	42	95.0	0.442	0.00000506	1125

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000782	0.000766
Ashkenazi Jewish	0.000199	0.000199
East Asian	0.000794	0.000779
Finnish	0.000188	0.000185
European (Non-Finnish)	0.00115	0.00113
Middle Eastern	0.000794	0.000779
South Asian	0.000499	0.000490
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' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF- 2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation 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. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress- activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity). {ECO:0000250|UniProtKB:P15442, ECO:0000250|UniProtKB:Q9QZ05, ECO:0000269|PubMed:25329545, ECO:0000269|PubMed:26102367}.
• Disease: DISEASE: Pulmonary venoocclusive disease 2, autosomal recessive (PVOD2) [MIM:234810]: A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension. {ECO:0000269|PubMed:24135949, ECO:0000269|PubMed:24292273}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Influenza A - Homo sapiens (human);Protein processing in endoplasmic reticulum - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Measles - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);regulation of eif2 (Consensus)

Intolerance Scores

• loftool: 0.866
• rvis_EVS: -0.72
• rvis_percentile_EVS: 14.27

Haploinsufficiency Scores

• pHI: 0.178
• hipred: Y
• hipred_score: 0.709
• ghis: 0.563

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.697

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Eif2ak4
• Phenotype: growth/size/body region phenotype; muscle phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system 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); reproductive system phenotype; hematopoietic system 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)

Gene ontology

• Biological process: DNA damage checkpoint;positive regulation of defense response to virus by host;adaptive immune response;T cell activation involved in immune response;positive regulation of adaptive immune response;regulation of translational initiation;protein phosphorylation;cell cycle arrest;learning;long-term memory;regulation of translational initiation by eIF2 alpha phosphorylation;viral translation;negative regulation of translational initiation in response to stress;negative regulation of CREB transcription factor activity;cellular response to amino acid starvation;cellular response to UV;eiF2alpha phosphorylation in response to endoplasmic reticulum stress;induction by virus of host autophagy;negative regulation by host of viral genome replication;negative regulation of neuron differentiation;negative regulation of translational initiation;protein autophosphorylation;defense response to virus;regulation of feeding behavior;regulation of eIF2 alpha phosphorylation by amino acid starvation;cellular response to cold;positive regulation of translational initiation in response to starvation;positive regulation of long-term synaptic potentiation;neuron projection extension;cellular response to leucine starvation
• Cellular component: polysome;cytosolic ribosome
• Molecular function: tRNA binding;protein kinase activity;protein serine/threonine kinase activity;eukaryotic translation initiation factor 2alpha kinase activity;ATP binding