MED15

Chr 22

mediator complex subunit 15

ENSG00000099917 UniProt: Q96RN5 OMIM: 607372

This protein is a component of the Mediator complex that serves as a coactivator for RNA polymerase II-dependent gene transcription and is required for cholesterol-dependent gene regulation. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. The gene is highly constrained against loss-of-function mutations (pLI >0.99), indicating that such variants are likely pathogenic when they occur.

OMIM ResearchSummary from RefSeq, UniProt

Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal signaling pathway

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.24

Clinical Summary— MED15

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 1.000

Z-score 5.96

OE 0.13 (0.07–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.53Z-score

OE missense 0.67 (0.61–0.74)

319 obs / 474.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.24)

0≤0.351.4

Missense OE?0.67 (0.61–0.74)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 7 / 54.5Missense obs/exp: 319 / 474.3Syn Z: -0.68

This gene — mechanism propensity

0.2897th %ile

GOF

0.2298th %ile

LOF

0.83top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.24

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.