MED27

Chr 9AR

mediator complex subunit 27

Also known as: CRAP34, CRSP34, CRSP8, MED3, NEDSCAC, TRAP37

NCBI Gene: 9442 ENSG00000160563 UniProt: Q6P2C8 OMIM: 605044

MED27 encodes a component of the Mediator complex that functions as a coactivator bridge between gene-specific regulatory proteins and the RNA polymerase II transcription machinery for nearly all RNA polymerase II-dependent genes. Mutations cause autosomal recessive neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia. The gene shows low constraint against loss-of-function variants (pLI 0.00002), suggesting tolerance to heterozygous loss.

OMIM ResearchSummary from RefSeq, OMIM, 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. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.021 OMIM phenotype

Clinical Summary— MED27

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Gene-Disease Validity (ClinGen)

neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 36 VUS of 65 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.000

Z-score 1.52

OE 0.60 (0.37–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.26Z-score

OE missense 0.73 (0.64–0.85)

131 obs / 178.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.37–1.02)

0≤0.351.4

Missense OE?0.73 (0.64–0.85)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 10 / 16.7Missense obs/exp: 131 / 178.5Syn Z: 0.03

ClinVar Variant Classifications

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

VUS36

Likely Benign7

Conflicting2

Pathogenic

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	3	0	6
Likely Pathogenic	0	0	0	0	0
VUS	6	30	0	0	36
Likely Benign	0	3	1	3	7
Benign	0	0	0	0	0
Conflicting	—				2
Total	8	34	4	3	51

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

34 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap MED27 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →