MRPL46

Chr 15

mitochondrial ribosomal protein L46

Also known as: C15orf4, LIECG2, P2ECSL, mL46

NCBI Gene: 26589 ENSG00000259494 UniProt: Q9H2W6

The protein is a component of the large 39S subunit of mitochondrial ribosomes, which synthesize proteins within mitochondria. Mutations cause autosomal recessive mitochondrial disorders affecting multiple organ systems, typically with early childhood onset. The gene shows minimal constraint against loss-of-function variants based on population data.

ResearchSummary from RefSeq

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. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.32

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.32LOEUF

pLI 0.000

Z-score 0.67

OE 0.81 (0.52–1.32)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.66Z-score

OE missense 1.15 (1.02–1.30)

175 obs / 152.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.81 (0.52–1.32)

0≤0.351.4

Missense OE?1.15 (1.02–1.30)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 12 / 14.8Missense obs/exp: 175 / 152.2Syn Z: -0.83

Background carrier burden — how many people carry a rare variant somewhere in MRPL46?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

462 rare PASS variants

Rare truncating (LoF)

1 in 2,200

75 rare PASS variants

Rare synonymous (reference)

1 in 280

179 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MRPL46. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 260	1 in 2,100
South Asian	~43k	1 in 120	1 in 1,300
Remaining (unassigned)	~30k	1 in 150	1 in 2,500
European (Finnish)	~27k	1 in 980	1 in 3,800
Admixed American	~22k	1 in 130	1 in 2,400
African / African American	~21k	1 in 72	1 in 1,900
East Asian	~20k	1 in 130	1 in 830
Ashkenazi Jewish	~13k	1 in 830	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 160	≈ 1 in 1,300

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓