MRPS16

protein-coding

mitochondrial ribosomal protein S16, 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 belongs to the ribosomal protein S16P family. The encoded protein is one of the most highly conserved ribosomal proteins between mammalian and yeast mitochondria. Three pseudogenes (located at 8q21.3, 20q13.32, 22q12-q13.1) for this gene have been described. [provided by RefSeq, Jul 2008]

MANE transcript

NM_016065.4

Inheritance

ClinVar variants

P:3U:50B:25

Top phenotype

Combined oxidative phosphorylation deficiency 2

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr10:73,248,843-73,252,693

External References & Databases

Ensembl (ENSG00000182180)

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

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPS16* and mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of June 16, 2022. The *MRPS16* gene encodes the mitochondrial ribosomal protein S16, a component of the small subunit of the mitochondrial ribosome. The *MRPS16* gene was first reported in relation to autosomal recessive mitochondrial disease in 2004 (PMID: 15505824). While various names have been given to the constellation of features seen in those with *MRPS16*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MRPS16* 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 one homozygous nonsense variant identified in one case from one publication (PMID: 15505824). This individual was of Bedouin descent and was born to consanguineous parents. Medical concerns included severe lactic acidosis, agenesis of the corpus callosum, ventriculomegaly, lethargy, and neonatal hypotonia. This individual died in the first few days of life. While this report pre-dated the comprehensive genomic sequencing, this GCEP agreed the biochemical and genetic evaluation performed was sufficient for this case to be included in this curation, and functional validation of the variant identified in this case was performed in a subsequent publication (PMID:18539099). Loss-of-function is implicated as a mechanism of disease. This gene-disease relationship is also supported by its known biochemical function that is shared with other genes associated with primary mitochondrial disease and functional alteration in patient cells (PMID: 15505824). In summary, there is limited evidence to support this gene-disease relationship. Although the total score (7) falls in the moderate range, only one case with primary mitochondrial disease has been reported, therefore this gene-disease association can only reach a limited classification at this time. 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 16, 2022 (SOP Version 9).

combined oxidative phosphorylation defect type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012510

Submitter: Orphanet

combined oxidative phosphorylation defect type 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012510

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012510

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 2AR

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

Comments: The described dysmorphic features may have been coincident (the patient was born to consanguineous parents) as relates to the mitochondrial disorder

Refs: 15505824

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRPS16 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 63

not specifiedTotal: 38

MRPS16-related disorderTotal: 4

Combined oxidative phosphorylation defect type 2Total: 4

MRPS16-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016065.4. 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	16 clinvar		17
missense			42 clinvar	8 clinvar	1 clinvar	51
nonsense		1 clinvar				1
start loss			1 clinvar			1
frameshift	1 clinvar		5 clinvar			6
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	1	2	50	24	1	78

Highest pathogenic variant AF is 0.00003283434

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016065.4	RefSeq	NP_057149.1	3	MANE Select
ENST00000372945.8	Ensembl	ENSP00000362036.3	3	MANE Select
NM_001410935.1	RefSeq	NP_001397864.1	3	Standard
ENST00000372940.3	Ensembl	ENSP00000362031.3	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ribosome - Homo sapiens (human)
Mitochondrial translation initiation
Translation
Metabolism of proteins
Mitochondrial translation elongation

Biological Process

translation
mitochondrial translation
mitochondrial translational elongation
mitochondrial translational termination

Molecular Function

structural constituent of ribosome
protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial small ribosomal subunit
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372945
Coding exons: 3
Length: 5942
Individuals with no LoFs: 125716
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125748
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.550	94	80.1	1.17	0.00000490	879
Missense (PolyPhen)		26	24.295	1.0702		314
Synonymous	-1.82	42	29.4	1.43	0.00000158	289
Loss of Function	0.788	2	3.62	0.553	1.54e-7	47

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00040	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Combined oxidative phosphorylation deficiency 2 (COXPD2) [MIM:610498]: A mitochondrial disease resulting in fatal neonatal metabolic acidosis with agenesis of the corpus callosum. {ECO:0000269|PubMed:15505824}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0794

Intolerance Scores

LoFtool: 0.689
RVIS EVS: 0.19
RVIS percentile EVS: 66.82

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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