GeneBe

MTFMT

protein-coding

mitochondrial methionyl-tRNA formyltransferase

Gene summary

The protein encoded by this nuclear gene localizes to the mitochondrion, where it catalyzes the formylation of methionyl-tRNA. [provided by RefSeq, Jun 2011]

MANE transcript

NM_139242.4

Inheritance

AR

ClinVar variants

P:39U:128B:68

Top phenotype

Combined oxidative phosphorylation deficiency 15

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr15:65,001,512-65,029,639

External References & Databases

Ensembl (ENSG00000103707)NCBI Gene (123263)OMIM (611766)HGNC:29666GenCCUniProt (Q96DP5)AlphaFoldClinVar (MTFMT)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~28.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation defect type 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013987

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013987

Submitter: Labcorp Genetics (formerly Invitae)

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MTFMT and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The MTFMT gene encodes mitochondrial methionyl-tRNA formyltransferase which catalyzes the formylation of the mitochondrial methionine tRNA (Met-tRNAMet). This formylation is required for the initiation of translation and elongation of mitochondrial protein synthesis. The MTFMT gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2011 (PMID: 21907147). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants identified in ten cases in four publications (PMIDs: 21907147, 23499752, 30911575, 24461907). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, functional alteration in non-patient cells, and rescue in patient cells (PMIDs: 29980628, 30087118, 21907147). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 2020 (SOP Version 7).

combined oxidative phosphorylation defect type 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013987

Submitter: G2P

combined oxidative phosphorylation defect type 15MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013987

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 15AR

Manifestation: Biochemical; Cardiovascular; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: Among other multi-systemic manifestations, the condition may include cardiac manifestations such as Wolff-Parkinson-White syndrome, and surveillance may allow early diagnosis and management

Refs: 21907147; 22499348; 23499752; 24461907Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTFMT variants in ClinVar

20 Conditions Cataloged
not providedTotal: 206
Inborn genetic diseasesTotal: 76
not specifiedTotal: 38
Combined oxidative phosphorylation defect type 15Total: 30
MTFMT-related disorderTotal: 18
Mitochondrial complex I deficiency, nuclear type 27Total: 10
MTFMT-Related DisordersTotal: 4
Leigh syndromeTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139242.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
47
clinvar
2
clinvar
 50
missense
2
clinvar
5
clinvar
118
clinvar
15
clinvar
4
clinvar
 144
nonsense
11
clinvar
4
clinvar
2
clinvar
 17
start loss
1
clinvar
2
clinvar
 3
frameshift
6
clinvar
4
clinvar
2
clinvar
 12
splice donor/acceptor (+/-2bp)
4
clinvar
5
clinvar
 9
Total2019128626235

Highest pathogenic variant AF is 0.0006967377

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_139242.4RefSeqNP_640335.29MANE Select
ENST00000220058.9EnsemblENSP00000220058.49MANE Select
ENST00000543678.1EnsemblENSP00000443754.13Standard
ENST00000558460.5EnsemblENSP00000452646.19Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • One carbon pool by folate - Homo sapiens (human)
  • Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
  • S-Adenosylhomocysteine (SAH) Hydrolase Deficiency
  • Methionine Metabolism
  • Folate malabsorption, hereditary

Biological Process

  • translational initiation
  • conversion of methionyl-tRNA to N-formyl-methionyl-tRNA

Molecular Function

  • methionyl-tRNA formyltransferase activity

Cellular Component

  • mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000220058
Coding exons
9
Length
27133
Individuals with no LoFs
124614
Homozygous LoFs
0
Heterozygous LoFs
47
Defined
124661
p
0.000189
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.4622141961.090.000009872467
Missense (PolyPhen)7069.7181.004810
Synonymous-0.3817671.91.060.00000399768
Loss of Function1.531421.70.6450.00000107252

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.000190.00019rare
European (Non-Finnish)0.000310.00031rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Formylates methionyl-tRNA in mitochondria. A single tRNA(Met) gene gives rise to both an initiator and an elongator species via an unknown mechanism (By similarity). {ECO:0000250}.;
Disease
DISEASE: Combined oxidative phosphorylation deficiency 15 (COXPD15) [MIM:614947]: An autosomal recessive, mitochondrial, neurologic disorder characterized by features of Leigh syndrome and combined oxidative phosphorylation deficiency. Clinical features include mild global developmental delay, white matter abnormalities, ataxia, incoordination, speech and reading difficulties, T2-weighted hyperintensities in the basal ganglia, corpus callosum, and brainstem. {ECO:0000269|PubMed:21907147}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:22499348}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.121

Intolerance Scores

LoFtool
0.817
RVIS EVS
0.71
RVIS percentile EVS
85.53

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.960

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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