EIF2A

protein-coding

eukaryotic translation initiation factor 2A, the group of WD repeat domain containing

Gene summary

This gene encodes a eukaryotic translation initiation factor that catalyzes the formation of puromycin-sensitive 80 S preinitiation complexes and the poly(U)-directed synthesis of polyphenylalanine at low concentrations of Mg2+. This gene should not be confused with eIF2-alpha (EIF2S1, Gene ID: 1965), the alpha subunit of the eIF2 translation initiation complex. Although both of these proteins function in binding initiator tRNA to the 40 S ribosomal subunit, the encoded protein does so in a codon-dependent manner, whereas eIF2 complex requires GTP. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

MANE transcript

NM_032025.5

Inheritance

ClinVar variants

U:73B:2

Top phenotype

EIF2A-related disorder

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr3:150,546,678-150,586,016

External References & Databases

Ensembl (ENSG00000144895)

Transcript & Mutation Effects

hg38 • Region Span ~39.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF2A variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 62

EIF2A-related disorderTotal: 1

Dystonia 33Total: 1

Marinesco-Sjögren syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032025.5. 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			1 clinvar			1
missense			69 clinvar	2 clinvar		71
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	73	2	0	75

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032025.5	RefSeq	NP_114414.2	14	MANE Select
ENST00000460851.6	Ensembl	ENSP00000417229.1	14	MANE Select
NM_001319043.2	RefSeq	NP_001305972.1	13	Standard
NM_001319044.2	RefSeq	NP_001305973.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Photodynamic therapy-induced unfolded protein response
VEGFA-VEGFR2 Signaling Pathway
Signaling events mediated by TCPTP
IL6
Ceramide signaling pathway

Biological Process

translational initiation
regulation of translation
protein phosphorylation
positive regulation of signal transduction
SREBP signaling pathway

Molecular Function

tRNA binding
translation initiation factor activity
protein binding
ribosome binding
cadherin binding

Cellular Component

extracellular space
cytoplasm
eukaryotic translation initiation factor 2 complex
cytosolic small ribosomal subunit
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000460851
Coding exons: 14
Length: 37565
Individuals with no LoFs: 124577
Homozygous LoFs: 0
Heterozygous LoFs: 61
Defined: 124638
p: 0.000245

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.10	229	281	0.816	0.0000132	3805
Missense (PolyPhen)		62	88.052	0.70413		1235
Synonymous	1.31	85	102	0.835	0.00000497	1089
Loss of Function	2.09	18	30.4	0.592	0.00000155	410

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00028	0.00028	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00059	0.00059	rare
Other	0.00051	0.00050	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions in the early steps of protein synthesis of a small number of specific mRNAs. Acts by directing the binding of methionyl-tRNAi to 40S ribosomal subunits. In contrast to the eIF- 2 complex, it binds methionyl-tRNAi to 40S subunits in a codon- dependent manner, whereas the eIF-2 complex binds methionyl-tRNAi to 40S subunits in a GTP-dependent manner. {ECO:0000269|PubMed:12133843}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.884
RVIS EVS: -0.2
RVIS percentile EVS: 38.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.560

Gene Damage Prediction

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