MRPL40

Chr 22

mitochondrial ribosomal protein L40

Also known as: L40mt, MRP-L22, MRP-L40, NLVCF, URIM, mL40

NCBI Gene: 64976 ENSG00000185608 UniProt: Q9NQ50 OMIM: 605089

The protein is a component of the large 39S subunit of mitochondrial ribosomes, which synthesize proteins within mitochondria. Deletions involving this gene may contribute to velo-cardio-facial syndrome and DiGeorge syndrome, which are autosomal dominant disorders affecting cardiac, facial, and immune system development. The gene shows tolerance to loss-of-function variants (pLI 0.05, LOEUF 0.79), suggesting that isolated mutations in this gene alone may not be sufficient to cause disease.

OMIM 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. Deletions in this gene may contribute to the etiology of velo-cardio-facial syndrome and DiGeorge syndrome. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.79

Clinical Summary— MRPL40

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

43 VUS of 67 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.053

Z-score 2.05

OE 0.35 (0.17–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.52Z-score

OE missense 1.14 (0.99–1.33)

122 obs / 106.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.35 (0.17–0.79)

0≤0.351.4

Missense OE?1.14 (0.99–1.33)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 4 / 11.5Missense obs/exp: 122 / 106.7Syn Z: -0.80

This gene — mechanism propensity

0.78top 25%

GOF

0.6247th %ile

LOF

0.2871th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

67 submitted variants in ClinVar

ClinVar

Classification Summary

VUS43

Likely Benign15

Benign6

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	42	0	0	43
Likely Benign	0	2	7	6	15
Benign	0	2	2	2	6
Total	1	46	9	8	64

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

392 pathogenic / likely-pathogenic (of 411) ClinVar copy-number / structural variants overlap MRPL40 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →