MED13

protein-coding

mediator complex subunit 13, the group of Mediator complex

Gene summary

This gene encodes a component of the mediator complex (also known as TRAP, SMCC, DRIP, or ARC), a transcriptional coactivator complex thought to be required for the expression of almost all genes. The mediator complex is recruited by transcriptional activators or nuclear receptors to induce gene expression, possibly by interacting with RNA polymerase II and promoting the formation of a transcriptional pre-initiation complex. The product of this gene is proposed to form a sub-complex with MED12, cyclin C, and CDK8 that can negatively regulate transactivation by mediator. [provided by RefSeq, Jul 2008]

Previous symbols:

THRAP1

MANE transcript

NM_005121.3

Inheritance

ClinVar variants

P:88U:513B:158

Top phenotype

Intellectual developmental disorder, autosomal dominant 61

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:61,942,605-62,065,278

External References & Databases

Ensembl (ENSG00000108510)

Transcript & Mutation Effects

hg38 • Region Span ~122.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder 61DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032485

Submitter: Ambry Genetics

intellectual developmental disorder 61STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032485

Submitter: G2P

intellectual developmental disorder 61STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032485

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder 61STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032485

Submitter: PanelApp Australia

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*MED13* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2018 (Snijders Blok et al., PMID: 29740699). The disorder is characterised by global developmental delay apparent in infancy with mildly impaired intellectual development, expressive speech delay, behavioural abnormalities (including autism spectrum disorder or attention deficit-hyperactivity disorder), nonspecific dysmorphic features, obstipation, ocular anomalies, and poor overall growth (PMID: 29740699). Fourteen variants (nonsense, frameshift, missense and in-frame indel) that have been reported in 15 probands in five publications are included in this curation (PMIDs: 25363768, 28263302, 29740699, 33258286, 33931951). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. In summary, there is definitive evidence supporting the relationship between *MED13* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 17, 2022 (SOP Version 9).

intellectual developmental disorder 61STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032485

Submitter: Illumina

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 61AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29740699

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MED13 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 350

Inborn genetic diseasesTotal: 268

Intellectual developmental disorder 61Total: 138

MED13-related disorderTotal: 78

not specifiedTotal: 54

See casesTotal: 4

Autosomal dominant isolated somatotropin deficiencyTotal: 3

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005121.3. 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			5 clinvar	51 clinvar	5 clinvar	61
missense	2 clinvar	16 clinvar	494 clinvar	95 clinvar	7 clinvar	614
nonsense	15 clinvar	8 clinvar	4 clinvar			27
start loss						0
frameshift	20 clinvar	17 clinvar	3 clinvar			40
splice donor/acceptor (+/-2bp)	6 clinvar	4 clinvar	7 clinvar			17
Total	43	45	513	146	12	759

Highest pathogenic variant AF is 0.0000013790459

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005121.3	RefSeq	NP_005112.2	30	MANE Select
ENST00000397786.7	Ensembl	ENSP00000380888.2	30	MANE Select
ENST00000583958.1	Ensembl	ENSP00000464131.1	3	Standard
ENST00000934727.1	Ensembl	ENSP00000604786.1	29	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
med13b	Danio rerio	Structure: cranial neural crest cell Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

med13b

Danio rerio

Structure: cranial neural crest cell

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone signaling pathway - Homo sapiens (human)
Developmental Biology
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription

Biological Process

regulation of transcription by RNA polymerase II
transcription initiation from RNA polymerase II promoter
intracellular steroid hormone receptor signaling pathway
androgen receptor signaling pathway
cholesterol homeostasis

Molecular Function

transcription coregulator activity
transcription coactivator activity
nuclear receptor transcription coactivator activity
signaling receptor activity
vitamin D receptor binding

Cellular Component

nucleus
nucleoplasm
membrane
mediator complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000397786
Coding exons: 30
Length: 122678
Individuals with no LoFs: 124782
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 124785
p: 0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.62	871	1.12e+3	0.779	0.0000556	14195
Missense (PolyPhen)		314	529.75	0.59273		6708
Synonymous	-1.38	422	388	1.09	0.0000191	4248
Loss of Function	9.19	0	98.4	0.00	0.00000492	1257

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.0000089	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

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. {ECO:0000269|PubMed:16595664}.;

Recessive Scores

pRec: 0.134

Intolerance Scores

LoFtool: 0.0136
RVIS EVS: -1.43
RVIS percentile EVS: 4.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.692

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium