LIME1

Chr 20

Lck interacting transmembrane adaptor 1

Also known as: LIME, dJ583P15.4

NCBI Gene: 54923 ENSG00000203896 UniProt: Q9H400 OMIM: 609809

The protein is a transmembrane adaptor that couples T-cell and B-cell antigen receptor activation to downstream signaling events including calcium mobilization and MAPK activation through recruitment of signaling molecules like PLCG2 and GRB2. Mutations cause autosomal recessive combined immunodeficiency affecting both T-cell and B-cell function. The gene shows low constraint to loss-of-function variation, consistent with a recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a transmembrane adaptor protein that links the T and B-cell receptor stimulation to downstream signaling pathways via its association with the Src family kinases Lck and Lyn, respectively. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Mar 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.65

Clinical Summary— LIME1

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.65LOEUF

pLI 0.000

Z-score 0.30

OE 0.88 (0.48–1.65)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.06Z-score

OE missense 0.76 (0.66–0.89)

121 obs / 158.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.88 (0.48–1.65)

0≤0.351.4

Missense OE?0.76 (0.66–0.89)

0≤0.61.4

Synonymous OE?0.62

0≤1.21.6

LoF obs/exp: 6 / 6.8Missense obs/exp: 121 / 158.5Syn Z: 2.63

This gene — mechanism propensity

0.7131th %ile

GOF

0.74top 25%

LOF

0.2872th %ile

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

GOFprediction above median

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.