EIF2B4

Chr 2

eukaryotic translation initiation factor 2B subunit delta

Also known as: EIF-2B, EIF2B, EIF2Bdelta, VWM4

NCBI Gene: 8890 ENSG00000115211 UniProt: Q9UI10

The protein functions as the delta subunit of eukaryotic initiation factor 2B (EIF2B), a GTP exchange factor essential for protein synthesis. Mutations cause leukoencephalopathy with vanishing white matter, sometimes accompanied by ovarian failure, through an autosomal recessive inheritance pattern. The high constraint scores (pLI 0.96, LOEUF 0.33) support that pathogenicity occurs predominantly through loss-of-function mechanisms affecting protein synthesis regulation.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtLeukoencephalopathy with vanishing white matter 4

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · leukoencephalopathy with vanishing white matter 4 · AR · ClinGen 2024
Strong · leukoencephalopathy with vanishing white matter · AR · Genomics England PanelApp
Strong · leukoencephalopathy with vanishing white matter 1 · AR · Labcorp Genetics (formerly Invitae)
Supportive · ovarioleukodystrophy · AR · Orphanet

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.33

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.961

Z-score 4.18

OE 0.14 (0.07–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.80Z-score

OE missense 0.87 (0.78–0.96)

257 obs / 295.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.33)

0≤0.351.4

Missense OE?0.87 (0.78–0.96)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 4 / 27.8Missense obs/exp: 257 / 295.6Syn Z: -1.35

Background carrier burden — how many people carry a rare variant somewhere in EIF2B4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

717 rare PASS variants

Rare truncating (LoF)

1 in 2,800

86 rare PASS variants

Rare synonymous (reference)

1 in 180

310 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EIF2B4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 170	1 in 2,900
South Asian	~43k	1 in 110	1 in 3,000
Remaining (unassigned)	~30k	1 in 110	1 in 4,900
European (Finnish)	~27k	1 in 410	≈ 1 in 26,000
Admixed American	~22k	1 in 72	1 in 1,200
African / African American	~21k	1 in 130	1 in 2,900
East Asian	~20k	1 in 75	1 in 1,300
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	1 in 120	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓