TUFM

protein-coding

Tu translation elongation factor, mitochondrial, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes a protein which participates in protein translation in mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency resulting in lactic acidosis and fatal encephalopathy. A pseudogene has been identified on chromosome 17. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003321.5

Inheritance

ClinVar variants

P:8U:98B:57

Top phenotype

Combined oxidative phosphorylation deficiency 4

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr16:28,842,411-28,846,348

External References & Databases

Ensembl (ENSG00000178952)

Transcript & Mutation Effects

hg38 • Region Span ~3.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation defect type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012534

Submitter: G2P

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TUFM* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 2, 2023. The *TUFM* gene encodes the mitochondrial translation elongation factor Tu, an enzyme that facilitates translation elongation by GTP-mediated binding of aminoacyl-tRNAs to the ribosomal A site, where codon recognition occurs during mitochondrial translation protein synthesis. *TUFM* was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 (PMID: 17160893). While various names could be given to the constellation of features seen in those with *TUFM*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TUFM* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes five variants in five probands across four publications (PMIDs: 17160893, 26741492, 28132884, 30903008). Affected individuals have clinical features falling in a spectrum, with those more severely affecting having early infantile-onset encephalopathy, brain anomalies, lactic acidosis, and risk of early death and others dilated cardiomyopathy and lactic acidosis without encephalopathy. Clinical features seen in affected individuals include Leigh syndrome spectrum disorders, lactic acidosis, dysplastic leukoencephalopathy, intrauterine growth restriction, hypertonia, spasticity, microcephaly, dilated cardiomyopathy, and respiratory failure. Dysmorphic features have also been noted (epicanthus, low-set ears, flat nasal bridge, high, arched palate, small hands and feet). Brain imaging showed diffuse cystic leukodystrophy, micropolygyria, and diffuse signal abnormality of the white matter in the centra semiovalia, putamina, and nuclei pallidi. Lab abnormalities include elevated lactate, pyruvate, ketones, transaminases, and ammonia. Mitochondrial respiratory chain enzyme deficiencies (complexes I and IV) are reported. Loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease and functional alteration studies in non-patient cells showing impaired binding to aminoacylated mitochondrial tRNAs and impaired mitochondrial translation (PMIDs: 19524667, 33340416). In summary, there is moderate evidence to support the relationship between *TUFM* and autosomal recessive primary mitochondrial disease. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 2, 2023 (SOP Version 9).

combined oxidative phosphorylation defect type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012534

Submitter: Orphanet

combined oxidative phosphorylation defect type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012534

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012534

Submitter: Labcorp Genetics (formerly Invitae)

inherited primary ovarian failureLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019852

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 4AR

Manifestation: Biochemical; Gastrointestinal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17160893

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUFM variants in ClinVar

6 Conditions Cataloged

not providedTotal: 159

Combined oxidative phosphorylation defect type 4Total: 44

Inborn genetic diseasesTotal: 37

not specifiedTotal: 15

TUFM-related disorderTotal: 11

Mitochondrial diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003321.5. 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			3 clinvar	48 clinvar	1 clinvar	52
missense	1 clinvar	3 clinvar	88 clinvar	8 clinvar		100
nonsense		1 clinvar				1
start loss			1 clinvar			1
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	3	5	98	56	1	163

Highest pathogenic variant AF is 0.000015490159

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003321.5	RefSeq	NP_003312.3	10	MANE Select
ENST00000313511.8	Ensembl	ENSP00000322439.3	10	MANE Select
NM_001365360.2	RefSeq	NP_001352289.1	10	Standard
ENST00000565012.1	Ensembl	ENSP00000455007.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Translation
Metabolism of proteins
Purine metabolism
Mitochondrial translation elongation
Mitochondrial translation

Biological Process

translational elongation
response to ethanol
mitochondrial translational elongation

Molecular Function

RNA binding
translation elongation factor activity
GTPase activity
protein binding
GTP binding

Cellular Component

mitochondrion
membrane
mitochondrial nucleoid
myelin sheath
synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313511
Coding exons: 10
Length: 3998
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.40	205	269	0.761	0.0000174	2918
Missense (PolyPhen)		62	108.29	0.57255		1122
Synonymous	0.0910	114	115	0.989	0.00000743	982
Loss of Function	2.37	7	17.8	0.393	0.00000101	220

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000088	0.000079	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis. Plays also a role in the regulation of autophagy and innate immunity. Recruits ATG5-ATG12 and NLRX1 at mitochondria and serves as a checkpoint of the RIG-I/DDX58-MAVS pathway. In turn, inhibits RLR-mediated type I interferon while promoting autophagy. {ECO:0000269|PubMed:22749352, ECO:0000269|PubMed:28407488}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 4 (COXPD4) [MIM:610678]: A mitochondrial disease resulting in neonatal lactic acidosis, rapidly progressive encephalopathy, severely decreased mitochondrial protein synthesis, and combined deficiency of mtDNA- related mitochondrial respiratory chain complexes. {ECO:0000269|PubMed:17160893}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.511
RVIS EVS: -0.4
RVIS percentile EVS: 26.73

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.923

Gene Damage Prediction

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