MRPL39

protein-coding

mitochondrial ribosomal protein L39, the group of Large subunit mitochondrial ribosomal proteins|Mitochondrial ribosomal proteins

Gene summary

Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q. [provided by RefSeq, Jul 2008]

MANE transcript

NM_017446.4

Inheritance

ClinVar variants

P:3U:59B:4

Top phenotype

Combined oxidative phosphorylation deficiency 59

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr21:25,585,656-25,607,517

External References & Databases

Ensembl (ENSG00000154719)

Transcript & Mutation Effects

hg38 • Region Span ~21.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPL39* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 29, 2024. The *MRPL39* gene encodes the mitochondrial ribosomal protein L39, one of 52 mitochondrial large ribosomal protein subunits that form the mitochondrial ribosome. *MRPL39* was first reported in relation to autosomal recessive primary mitochondrial disease in 2023 (PMID:18771761), in three affected individuals presenting with a broad phenotype spectrum of severe disease including Leigh syndrome spectrum (LSS). Clinical features included developmental delay, hypotonia, hypertrophic cardiomyopathy, feeding difficulty and faltering growth, together with brain abnormalities detected by MRI and elevate blood lactate. The age of onset ranged from birth to early infancy and cases showed variability in the severity of the clinical course. While various names have been given to the constellation of features seen in those with *MRPL39*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MRPL39* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting the gene-disease relationship between *MRPL39* and primary mitochondrial disease includes case-level data and experimental data. This curation includes four unique variants in three probands from one publication (PMID: 18771761). Variant types included one missense, one frameshift, and two splice region variants. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and functional alteration observed in fibroblasts from affected individuals (PMIDs: 33340416; 18771761). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, 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 January 29, 2024 (SOP Version 9).

combined oxidative phosphorylation deficiency 59STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957992

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 59AR

Manifestation: Biochemical; Cardiovascular; Neurologic

Intervention: Cardiovascular

Rationale: The condition has been described as including hypertrophic cardiomyopathy, and awareness may allow early recognition and management

Refs: 37133451

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRPL39 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 49

not providedTotal: 9

Combined oxidative phosphorylation deficiency 59Total: 6

Mitochondrial diseaseTotal: 5

Leigh syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017446.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	2 clinvar		3
missense		1 clinvar	52 clinvar	1 clinvar		54
nonsense		1 clinvar	2 clinvar			3
start loss			1 clinvar	1 clinvar		2
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	3	59	4	0	66

Highest pathogenic variant AF is 0.0002628525

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017446.4	RefSeq	NP_059142.3	10	MANE Select
ENST00000352957.9	Ensembl	ENSP00000284967.7	10	MANE Select
NM_080794.4	RefSeq	NP_542984.3	11	Standard
ENST00000307301.11	Ensembl	ENSP00000305682.7	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mitochondrial translation initiation
Translation
Metabolism of proteins
Mitochondrial translation elongation
Mitochondrial translation termination

Biological Process

mitochondrial translational elongation
mitochondrial translational termination

Molecular Function

nucleotide binding
RNA binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial ribosome
mitochondrial large ribosomal subunit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307301
Coding exons: 11
Length: 21862
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 77
Defined: 125748
p: 0.000306

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.373	206	191	1.08	0.00000979	2297
Missense (PolyPhen)		50	53.466	0.93518		711
Synonymous	-0.771	74	66.0	1.12	0.00000348	647
Loss of Function	1.90	12	21.5	0.557	0.00000118	263

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00050	0.00049	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00040	0.00040	rare
South Asian	0.00037	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.874
RVIS EVS: 0.22
RVIS percentile EVS: 68.44

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.587

Gene Damage Prediction

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