EIF2B5

eukaryotic translation initiation factor 2B subunit epsilon

Basic information

Region (hg38): 3:184135038-184146127

Links

ENSG00000145191 ∙ NCBI:8893 ∙ OMIM:603945 ∙ HGNC:3261 ∙ Uniprot:Q13144 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• leukoencephalopathy with vanishing white matter (Definitive), mode of inheritance: AR
• leukoencephalopathy with vanishing white matter 1 (Definitive), mode of inheritance: AR
• leukoencephalopathy with vanishing white matter (Strong), mode of inheritance: AR
• ovarioleukodystrophy (Supportive), mode of inheritance: AR
• leukoencephalopathy with vanishing white matter 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leukoencephalopathy with vanishing white matter 5	AR	Obstetric	Individuals with Ovarioleukodystrophy may suffer from premature ovarian failure, and measures to allow reproduction (eg,through egg preservation) may be desired	Endocrine; Neurologic; Obstetric	11704758; 12325082; 11835386; 14694060; 12707859; 14566705; 15054402; 15136673; 15136690; 15776425; 18263758; 19625339; 20301435; 20975056; 21676421; 22699478
The evidence is unclear, but it is possible that certain circumstances may aggravate the condition and accelerate neurological decline, including head trauma (children may benefit from wearing helmets), contact sports, and stressful situations (including high body temperature, and prophylactic measures and rapid treatment related to infections may be beneficial)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EIF2B5 gene.

• not provided (44 variants)
• Vanishing white matter disease (13 variants)
• Leukoencephalopathy with vanishing white matter 5 (3 variants)
• Inborn genetic diseases (2 variants)
• See cases (2 variants)
• Dystonic disorder;Developmental regression;Leukodystrophy;Abnormal cerebral white matter morphology (1 variants)
• EIF2B5-related disorder (1 variants)
• Leukoencephalopathy with vanishing white matter 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EIF2B5 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			1	259		260
missense	13	30	140	6	1	190
nonsense	17	1	1			19
start loss		1				1
frameshift	20		1			21
inframe indel			1			1
splice donor/acceptor (+/-2bp)		8				8
splice region			6	41	1	48
non coding			7	109	13	129
Total	50	40	151	374	14

Highest pathogenic variant AF is 0.000269

Variants in EIF2B5

This is a list of pathogenic ClinVar variants found in the EIF2B5 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-184135073-A-G		Vanishing white matter disease	Benign (Nov 11, 2018)
3-184135183-C-A		Vanishing white matter disease	Uncertain significance (Jun 14, 2016)
3-184135231-T-C		Vanishing white matter disease	Uncertain significance (Jun 14, 2016)
3-184135233-T-G		Vanishing white matter disease	Uncertain significance (Jun 14, 2016)
3-184135236-G-C		Vanishing white matter disease	Uncertain significance (Jun 14, 2016)
3-184135269-C-T		Vanishing white matter disease	Uncertain significance (Jun 14, 2016)
3-184135283-C-G		Vanishing white matter disease	Uncertain significance (Jun 14, 2016)
3-184135287-G-A			Uncertain significance (Feb 01, 2022)
3-184135380-A-G		EIF2B5-related disorder	Likely benign (Jan 26, 2022)
3-184135388-G-C			Likely pathogenic (Feb 11, 2020)
3-184135390-C-T		Vanishing white matter disease	Conflicting classifications of pathogenicity (Jun 19, 2021)
3-184135391-G-A			Likely benign (Aug 11, 2023)
3-184135392-G-A			Uncertain significance (Oct 17, 2022)
3-184135395-C-T			Uncertain significance (Jul 28, 2022)
3-184135397-T-C			Likely benign (Sep 21, 2023)
3-184135400-A-G			Likely benign (Oct 23, 2022)
3-184135403-G-A			Likely benign (Aug 06, 2022)
3-184135406-G-A			Likely benign (Nov 04, 2023)
3-184135406-G-C			Likely benign (Feb 28, 2022)
3-184135409-G-A			Likely benign (Jan 06, 2023)
3-184135409-G-T			Likely benign (Oct 15, 2023)
3-184135412-T-G			Likely benign (Nov 13, 2023)
3-184135418-G-A			Likely benign (May 22, 2023)
3-184135422-G-A			Uncertain significance (Mar 20, 2022)
3-184135427-T-C			Likely benign (Nov 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EIF2B5	protein_coding	protein_coding	ENST00000273783	16	549721

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0642	0.936	125731	0	17	125748	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.777	346	389	0.889	0.0000231	4710
Missense in Polyphen		42	63.524	0.66117		804
Synonymous	0.439	143	150	0.954	0.00000843	1403
Loss of Function	4.25	10	38.5	0.260	0.00000246	415

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000177	0.000177
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000703	0.0000703
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.
• Disease: DISEASE: Leukodystrophy with vanishing white matter (VWM) [MIM:603896]: A leukodystrophy that occurs mainly in children. Neurological signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy and relatively preserved mental abilities. The disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. While childhood onset is the most common form of the disorder, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood. Some females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy. {ECO:0000269|PubMed:11704758, ECO:0000269|PubMed:12325082, ECO:0000269|PubMed:12707859, ECO:0000269|PubMed:15776425, ECO:0000269|PubMed:19158808, ECO:0000269|PubMed:21484434}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: RNA transport - Homo sapiens (human);Translation Factors;MicroRNAs in cardiomyocyte hypertrophy;skeletal muscle hypertrophy is regulated via akt-mtor pathway;Recycling of eIF2:GDP;Eukaryotic Translation Initiation;Translation;Metabolism of proteins;regulation of eif2;Cap-dependent Translation Initiation (Consensus)

Recessive Scores

• pRec: 0.159

Intolerance Scores

• loftool: 0.0221
• rvis_EVS: -0.89
• rvis_percentile_EVS: 10.43

Haploinsufficiency Scores

• pHI: 0.513
• hipred: Y
• hipred_score: 0.806
• ghis: 0.603

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Eif2b5
• Phenotype: homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; growth/size/body region 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); vision/eye 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); immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: ovarian follicle development;translational initiation;aging;response to heat;response to glucose;response to lithium ion;astrocyte development;oligodendrocyte development;hippocampus development;response to endoplasmic reticulum stress;myelination;positive regulation of apoptotic process;response to peptide hormone;positive regulation of translational initiation;astrocyte differentiation;T cell receptor signaling pathway
• Cellular component: nucleus;cytoplasm;cytosol;eukaryotic translation initiation factor 2B complex
• Molecular function: translation initiation factor activity;guanyl-nucleotide exchange factor activity;protein binding;translation initiation factor binding