MED25
protein-codingmediator complex subunit 25, the group of Mediator complex|MicroRNA protein coding host genes
Gene summary
This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2. [provided by RefSeq, Apr 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~22.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011570
Submitter: ClinGen
In association with a late-onset, axonal, sensorimotor polyneuropathy, MED25 was first described in a Costa Rican family with an extended multi-generational, autosomal recessive pedigree (Leal et al., 2001; PMID: 11112660; Berghoff et al., 2004; PMID: 15099588; Leal et al., 2009; PMID: 19290556). Since its first description, however, no further associated CMT families have been published. Contrarily, the only reported variant has been found in a homozygous state in 4 unaffected individuals (GnomAD). Re-assessing the first and only reported family by WES, Leal et al. identified a homozygous stop mutation in PNKP, a gene that is located in the same linkage region (Leal et al., 2018; PMID: 11112660). The authors identified 5 further families carrying biallelic loss-of-function mutations in PNKP as well, pointing towards the pathogenicity of this gene over MED25. With no further strong experimental evidence supporting the gene-disease relationship between MED25 and CMT2B, we thereby classify the gene as “DISPUTED”. The likewise associated, autosomal recessive Basel-Vanagaite-Smirin-Yosef syndrome has a congenital age at onset and does not include neuropathy in its phenotypic spectrum.
Inheritance Pattern: AR
Disease ID:MONDO:0014643
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014643
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0019502
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014643
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014643
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014643
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Neurologic; Ophthalmologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MED25 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_030973.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 11 | 240 | 4 | 255 | ||
| missense | 1 | 5 | 292 | 10 | 308 | |
| nonsense | 2 | 6 | 8 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 9 | 22 | 32 | ||
| splice donor/acceptor (+/-2bp) | 1 | 8 | 9 | |||
| Total | 2 | 18 | 339 | 250 | 4 | 613 |
Highest pathogenic variant AF is 0.00013089883
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_112235.2 | 18 | MANE Select | |
| Ensembl | ENSP00000326767.5 | 18 | MANE Select | |
| RefSeq | NP_001365284.1 | 18 | Standard | |
| Ensembl | ENSP00000437496.1 | 13 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| med25 | Danio rerio | Structure: peripheral neuron Quality: branchiness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Developmental Biology
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
- Transcriptional regulation of white adipocyte differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- transcription initiation from RNA polymerase II promoter
- positive regulation of chromatin binding
- positive regulation of transcription by RNA polymerase II
- negative regulation of fibroblast proliferation
Molecular Function
- protein binding
- transcription factor binding
- retinoic acid receptor binding
- retinoid X receptor binding
Cellular Component
- nucleoplasm
- mediator complex
- nuclear transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000312865
- Coding exons
- 18
- Length
- 20535
- Individuals with no LoFs
- 125666
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 82
- Defined
- 125748
- p
- 0.000326
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.25 | 380 | 455 | 0.835 | 0.0000288 | 4691 |
| Missense (PolyPhen) | 124 | 171.02 | 0.72505 | 1798 | ||
| Synonymous | -2.45 | 247 | 203 | 1.22 | 0.0000145 | 1631 |
| Loss of Function | 3.28 | 17 | 39.1 | 0.435 | 0.00000201 | 403 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00033 | 0.00025 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0.00021 | 0.00020 | rare |
| East Asian | 0.00088 | 0.00087 | rare |
| Finnish | 0.000048 | 0.000046 | rare |
| European (Non-Finnish) | 0.00033 | 0.00031 | rare |
| South Asian | 0.00043 | 0.00042 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: 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 RARA/RXRA-mediated transcription. {ECO:0000269|PubMed:14657022, ECO:0000269|PubMed:14983011, ECO:0000269|PubMed:17641689}.;
- Disease
- DISEASE: Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) [MIM:616449]: An autosomal recessive syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability. {ECO:0000269|PubMed:25792360}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.148
Intolerance Scores
- LoFtool
- 0.433
- RVIS EVS
- -0.53
- RVIS percentile EVS
- 20.78
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.517
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |