LYRM1

Chr 16

LYR motif containing 1

Also known as: A211C6.1

NCBI Gene: 57149 ENSG00000102897 UniProt: O43325

The protein promotes cell proliferation and inhibits apoptosis in preadipocytes, contributing to adipose tissue homeostasis. Mutations cause autosomal recessive mitochondrial complex III deficiency, presenting with severe early-onset neurodegeneration, developmental delay, and multisystem involvement. This gene is extremely intolerant to loss-of-function variants, indicating that complete protein loss is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the mitochondrial leucine/tyrosine/arginine motif family of proteins. Proteins of this family are short polypeptides that contain a leucine/tyrosine/arginine motif near the N-terminus. This gene is widely expressed with high levels in omental adipose tissue of obese individuals. In adipose tissue, the protein is localized to the nucleus where it promotes preadipocyte proliferation and lowers the rate of apoptosis to regulate adipose tissue homeostasis. Overexpression of this gene in adipocytes causes abnormal mitochondrial morphology and mitochondrial dysfunction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.92

Clinical Summary— LYRM1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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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?

1.92LOEUF

pLI 0.000

Z-score -1.11

OE 1.43 (0.88–1.92)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.42Z-score

OE missense 1.14 (0.95–1.37)

80 obs / 70.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.43 (0.88–1.92)

0≤0.351.4

Missense OE?1.14 (0.95–1.37)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 11 / 7.7Missense obs/exp: 80 / 70.2Syn Z: 0.64

This gene — mechanism propensity

0.6842th %ile

GOF

0.6540th %ile

LOF

0.3648th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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.