LYRM4

Chr 6

LYR motif containing 4

Also known as: C6orf149, CGI-203, COXPD19, ISD11

NCBI Gene: 57128 ENSG00000214113 UniProt: Q9HD34

This protein stabilizes the core iron-sulfur cluster assembly complex and regulates the cysteine desulfurase activity of NFS1, participating in the synthesis of [2Fe-2S] clusters essential for mitochondrial and cytoplasmic iron-sulfur protein biogenesis. Mutations cause autosomal recessive defects in iron-sulfur cluster assembly, leading to mitochondrial dysfunction affecting multiple organ systems. The gene shows moderate constraint against loss-of-function variants, consistent with its essential role in cellular iron metabolism.

ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is found in both mitochondria and the nucleus, where it binds cysteine desulfurase and helps free inorganic sulfur for Fe/S clusters. Disruption of this gene negatively impacts mitochondrial and cytosolic iron homeostasis. [provided by RefSeq, Sep 2016]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.54

Clinical Summary— LYRM4

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Population Constraint (gnomAD)

Low constraint (pLI 0.20) — 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?

1.54LOEUF

pLI 0.200

Z-score 0.98

OE 0.36 (0.13–1.54)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.36Z-score

OE missense 0.86 (0.67–1.10)

43 obs / 50.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.13–1.54)

0≤0.351.4

Missense OE?0.86 (0.67–1.10)

0≤0.61.4

Synonymous OE?0.78

0≤1.21.6

LoF obs/exp: 1 / 2.8Missense obs/exp: 43 / 50.2Syn Z: 0.74

This gene — mechanism propensity

0.86top 5%

GOF

0.6736th %ile

LOF

0.2677th %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.