MED14

Chr X

mediator complex subunit 14

Also known as: CRSP150, CRSP2, CSRP, CXorf4, DRIP150, EXLM1, RGR1, TRAP170

NCBI Gene: 9282 ENSG00000180182 UniProt: O60244 OMIM: 300182

The protein is a component of the Mediator complex that functions as a coactivator for RNA polymerase II-dependent gene transcription, serving as a bridge between gene-specific regulatory proteins and the basal transcription machinery. Mutations cause X-linked intellectual disability with variable additional features including seizures, behavioral problems, and dysmorphic features. This gene is extremely intolerant to loss-of-function variants and escapes X-inactivation, which may contribute to phenotypic expression in carrier females.

OMIM ResearchSummary from RefSeq, UniProt

The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein contains a bipartite nuclear localization signal. This gene is known to escape chromosome X-inactivation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 6.54

OE 0.02 (0.01–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.13Z-score

OE missense 0.49 (0.44–0.54)

252 obs / 516.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.09)

0≤0.351.4

Missense OE?0.49 (0.44–0.54)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 1 / 51.7Missense obs/exp: 252 / 516.3Syn Z: 1.57

Background carrier burden — how many people carry a rare variant somewhere in MED14?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

784 rare PASS variants

Rare truncating (LoF)

1 in 43,000

13 rare PASS variants

Rare synonymous (reference)

1 in 140

422 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MED14. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 180	1 in 41,000
South Asian	~36k	1 in 91	≈ 1 in 32,000
Remaining (unassigned)	~31k	1 in 110	none seen
European (Finnish)	~27k	1 in 2,200	≈ 1 in 24,000
Admixed American	~23k	1 in 99	≈ 1 in 9,100
African / African American	~21k	1 in 110	none seen
East Asian	~20k	1 in 110	none seen
Ashkenazi Jewish	~13k	1 in 2,400	none seen
Middle Eastern	~2,758	1 in 88	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 28 of 31 coding exons well covered in gnomAD exomes; exons 1, 10, 19 marginal. Genomes: all 31.? see exons ↓