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…

LOFmechanismADLOEUF 0.181 OMIM phenotype

Clinical Summary— MED12L

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Gene-Disease Validity (ClinGen)

Nizon-Isidor syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

39 unique Pathogenic / Likely Pathogenic· 675 VUS of 897 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.2997th %ile

GOF

0.2597th %ile

LOF

0.83top 5%

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

LOFprediction above median · 1 literature citation · 90% of P/LP variants are LoF · LOEUF 0.18

Literature Evidence

LOFOverall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect.1

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

References

1.PMID 31155615 ↗

ClinVar Variant Classifications

897 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic27

VUS675

Likely Benign111

Benign20

Conflicting13

Pathogenic

Likely Pathogenic

675

VUS

111

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	1	0	0	12
Likely Pathogenic	24	3	0	0	27
VUS	9	653	11	2	675
Likely Benign	0	43	7	61	111
Benign	0	5	7	8	20
Conflicting	—				13
Total	44	705	25	71	858

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap MED12L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →