GUF1

Chr 4AR

GTP binding elongation factor GUF1

Also known as: DEE40, EF-4, EF4, EIEE40

NCBI Gene: 60558 ENSG00000151806 UniProt: Q8N442 OMIM: 617064

GUF1 encodes a mitochondrial GTPase that promotes protein synthesis by ensuring translation fidelity through catalyzing backward translocation of tRNAs on improperly positioned ribosomes. Mutations cause developmental and epileptic encephalopathy 40 with early infantile onset through autosomal recessive inheritance. The gene is extremely intolerant to loss-of-function variants, indicating it is essential for normal cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a GTPase that triggers back-translocation of the elongating ribosome during mitochondrial protein synthesis. The protein contains a highly conserved C-terminal domain not found in other GTPases that facilitates tRNA binding. The encoded protein is thought to prevent misincorporation of amino acids in stressful, suboptimal conditions. An allelic variant in this gene has been associated with early infantile epileptic encephalopathy-40. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.141 OMIM phenotype

Clinical Summary— GUF1

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 305 VUS of 509 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.000

Z-score 0.90

OE 0.84 (0.63–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.98 (0.89–1.07)

325 obs / 332.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.63–1.14)

0≤0.351.4

Missense OE?0.98 (0.89–1.07)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 30 / 35.8Missense obs/exp: 325 / 332.8Syn Z: 0.22

This gene — mechanism propensity

0.6745th %ile

GOF

0.6149th %ile

LOF

0.4135th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

509 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS305

Likely Benign146

Benign21

Conflicting11

Pathogenic

305

VUS

146

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	45	239	17	4	305
Likely Benign	1	8	68	69	146
Benign	1	5	13	2	21
Conflicting	—				11
Total	47	253	98	75	484

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap GUF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →