MED12L

Chr 3AD

mediator complex subunit 12L

Also known as: NIZIDS, NOPAR, TNRC11L, TRALP, TRALPUSH

NCBI Gene: 116931 ENSG00000144893 UniProt: Q86YW9 OMIM: 611318

The protein is a component of the Mediator complex that functions as a coactivator for RNA polymerase II-dependent gene transcription by bridging gene-specific regulatory proteins with the basal transcription machinery. Mutations cause Nizon-Isidor syndrome with autosomal dominant inheritance. This gene is extremely intolerant to loss-of-function variants, indicating that proper protein dosage is critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Nizon-Isidor syndromeMIM #618872

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Nizon-Isidor syndrome · AD · ClinGen 2024

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

0.18

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 9.13

OE 0.12 (0.08–0.18)

Highly constrained

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

Missense Constraint?

3.13Z-score

OE missense 0.74 (0.70–0.79)

869 obs / 1170.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.12 (0.08–0.18)

0≤0.351.4

Missense OE?0.74 (0.70–0.79)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 15 / 125.2Missense obs/exp: 869 / 1170.5Syn Z: -0.46

Background carrier burden — how many people carry a rare variant somewhere in MED12L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

2,332 rare PASS variants

Rare truncating (LoF)

1 in 1,900

123 rare PASS variants

Rare synonymous (reference)

1 in 35

1,048 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MED12L. 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)	~556k	1 in 56	1 in 2,700
South Asian	~43k	1 in 35	1 in 1,300
Remaining (unassigned)	~30k	1 in 31	1 in 860
European (Finnish)	~27k	1 in 82	1 in 3,300
Admixed American	~22k	1 in 32	1 in 1,900
African / African American	~21k	1 in 42	1 in 1,000
East Asian	~20k	1 in 34	1 in 1,600
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 32	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): 39 of 44 coding exons well covered in gnomAD exomes; exons 15, 18, 26, 32, 36 marginal. Genomes: all 44.? see exons ↓