MRPS28

protein-coding

mitochondrial ribosomal protein S28, 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 that has been called mitochondrial ribosomal protein S35 in the literature. [provided by RefSeq, Jul 2008]

MANE transcript

NM_014018.3

Inheritance

ClinVar variants

P:1U:38B:13

Top phenotype

Combined oxidative phosphorylation deficiency 47

gnomAD constraint

pLI —, LoF o/e 1.19

Max pathogenic AF

—

Genomic locus

chr8:79,918,717-80,030,289

External References & Databases

Ensembl (ENSG00000147586)

Transcript & Mutation Effects

hg38 • Region Span ~111.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPS28* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 20, 2024. The *MRPS28* gene encodes the mitochondrial ribosomal protein S28, a component of the small subunit of the mitochondrial ribosome. The first and only report of *MRPS28* in relation to autosomal recessive primary mitochondrial disease was in 2019 (PMID: 30566640; case was first described in PMID: 8989468), in a 30-year-old man who presented in infancy with failure to thrive, hypoglycemia, dysmorphic facial features, sensorineural hearing loss, and cataracts. By age 24 years, he had elevated liver enzymes and globus pallidus lesions with cerebellar atrophy noted on brain imaging. Muscle biopsy showed reduced activities of the mitochondrial respiratory chain enzymes. He had compound heterozygous (missense and frameshift) variants in *MRPS28*. While various names could be given to the constellation of features seen in those with *MRPS28*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MRPS28 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 included the two variants noted above in one case from one publication (PMID: 30566640). The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of MRPS28 in mitochondrial translation, and rescue studies performed in patient cells (PMID: 30566640). In summary, there is limited 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 June 20, 2024 (SOP Version 10).

combined oxidative phosphorylation deficiency 47LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033537

Submitter: Ambry Genetics

combined oxidative phosphorylation deficiency 47LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033537

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation deficiency 47LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033537

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 47AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Genitourinary; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

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: 30566640

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRPS28 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 37

MRPS28-related disorderTotal: 11

not providedTotal: 6

Combined oxidative phosphorylation deficiency 47Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014018.3. 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				5 clinvar		5
missense	1 clinvar		36 clinvar	5 clinvar	3 clinvar	45
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	0	38	10	3	52

Highest pathogenic variant AF is 6.8808447e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014018.3	RefSeq	NP_054737.1	3	MANE Select
ENST00000276585.9	Ensembl	ENSP00000276585.4	3	MANE Select
ENST00000518271.1	Ensembl	ENSP00000427846.1	4	Standard
ENST00000518371.2	Ensembl	ENSP00000476135.1	2	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

biological_process
mitochondrial translational elongation
mitochondrial translational termination

Molecular Function

RNA binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial small ribosomal subunit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000276585
Coding exons: 3
Length: 111573
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125747
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0263	104	103	1.01	0.00000503	1196
Missense (PolyPhen)		28	36.596	0.76512		417
Synonymous	-1.23	51	41.0	1.24	0.00000191	389
Loss of Function	-0.398	6	5.04	1.19	2.10e-7	70

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0972

Intolerance Scores

LoFtool: 0.787
RVIS EVS: 0.9
RVIS percentile EVS: 89.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.248

Gene Damage Prediction

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