MTRFR

Chr 12AR

mitochondrial translation release factor in rescue

Also known as: C12orf65, COXPD7, SPG55, mtRF-R

NCBI Gene: 91574 ENSG00000130921 UniProt: Q9H3J6 OMIM: 613541

The protein contributes to peptide chain termination in mitochondrial translation machinery and functions as part of a mitoribosome-associated quality control pathway that ejects unfinished nascent chains from stalled ribosomes. Mutations cause combined oxidative phosphorylation deficiency 7 and spastic paraplegia 55 through autosomal recessive inheritance, resulting in decreased mitochondrial translation and reduced levels of oxidative phosphorylation complexes that lead to encephalomyopathy.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This nuclear gene encodes a mitochondrial matrix protein that appears to contribute to peptide chain termination in the mitochondrial translation machinery. Two different 1 bp deletions (resulting in the same premature stop codon)result in decreased mitochondrial translation, decreased levels of oxidative phosphorylation complexes and encepthalomyopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.912 OMIM phenotypes

Clinical Summary— MTRFR

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 89 VUS of 175 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MTRFR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.209

Z-score 1.74

OE 0.29 (0.12–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.43Z-score

OE missense 1.13 (0.96–1.33)

102 obs / 90.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.29 (0.12–0.91)

0≤0.351.4

Missense OE?1.13 (0.96–1.33)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 2 / 6.9Missense obs/exp: 102 / 90.4Syn Z: 1.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMTRFR-related combined oxidative phosphorylation deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7132th %ile

GOF

0.7126th %ile

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

175 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic10

VUS89

Likely Benign42

Benign9

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	0	2	0	15
Likely Pathogenic	9	1	0	0	10
VUS	3	60	26	0	89
Likely Benign	0	0	14	28	42
Benign	0	1	7	1	9
Conflicting	—				9
Total	25	62	49	29	174

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap MTRFR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →