MRPS34

protein-coding

mitochondrial ribosomal protein S34, the group of Small 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 28S subunit protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MANE transcript

NM_023936.2

Inheritance

ClinVar variants

P:11U:64B:45

Top phenotype

Combined oxidative phosphorylation deficiency 32

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr16:1,771,890-1,773,150

External References & Databases

Ensembl (ENSG00000074071)

Transcript & Mutation Effects

hg38 • Region Span ~1.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between MRPS34 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The MRPS34 gene encodes the mitochondrial ribosomal protein S34, a component of the small subunit of the mitochondrial ribosome. The MRPS34 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2017 (PMID: 29625026). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants identified in four unrelated cases from one publication (PMID: 28777931). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression data, functional alteration in patient cells, and animal models (PMIDs: 28777931, 25816300, 25613900). 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel December 9, 2019 (SOP Version 7).

combined oxidative phosphorylation deficiency 32STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054654

Submitter: G2P

combined oxidative phosphorylation deficiency 32STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054654

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation deficiency 32STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054654

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 32AR

Manifestation: Biochemical; 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: 28777931

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRPS34 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 89

Inborn genetic diseasesTotal: 42

MRPS34-related disorderTotal: 16

Combined oxidative phosphorylation deficiency 32Total: 11

not specifiedTotal: 6

Leigh syndromeTotal: 1

Mitochondrial diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_023936.2. 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				34 clinvar	3 clinvar	37
missense		2 clinvar	62 clinvar	6 clinvar	2 clinvar	72
nonsense	1 clinvar	2 clinvar				3
start loss	1 clinvar					1
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	2 clinvar			5
Total	4	7	64	40	5	120

Highest pathogenic variant AF is 0.0012406207

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_023936.2	RefSeq	NP_076425.1	3	MANE Select
ENST00000397375.7	Ensembl	ENSP00000380531.3	3	MANE Select
NM_001300900.2	RefSeq	NP_001287829.1	3	Standard
ENST00000177742.7	Ensembl	ENSP00000177742.3	3	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 translation
mitochondrial translational elongation
mitochondrial translational termination

Molecular Function

structural constituent of ribosome

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial small ribosomal subunit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397375
Coding exons: 3
Length: 1266
Individuals with no LoFs: 124955
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 124962
p: 0.0000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.43	135	95.7	1.41	0.00000463	1345
Missense (PolyPhen)		49	37.535	1.3054		545
Synonymous	-1.76	55	40.7	1.35	0.00000210	446
Loss of Function	0.333	4	4.79	0.836	2.06e-7	68

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000036	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for mitochondrial translation, plays a role in maintaining the stability of the small ribosomal subunit and the 12S rRNA that are required for mitoribosome formation. {ECO:0000269|PubMed:28777931}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 32 (COXPD32) [MIM:617664]: An autosomal recessive disorder due to deficiency of mitochondrial respiratory chain complexes, I, III and IV, and characterized by delayed psychomotor development and neurodevelopmental regression. Additional variable symptoms include poor or absent speech, inability to walk, and abnormal movements. {ECO:0000269|PubMed:28777931}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.245

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.905

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High