MED17

protein-coding

mediator complex subunit 17, the group of Mediator complex

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

CRSP6

MANE transcript

NM_004268.5

Inheritance

ClinVar variants

P:87U:186B:248

Top phenotype

Microcephaly, postnatal progressive, with seizures and brain atrophy

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr11:93,784,227-93,814,963

External References & Databases

Ensembl (ENSG00000042429)

Transcript & Mutation Effects

hg38 • Region Span ~30.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile cerebral and cerebellar atrophy with postnatal progressive microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013351

Submitter: PanelApp Australia

infantile cerebral and cerebellar atrophy with postnatal progressive microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013351

Submitter: Orphanet

infantile cerebral and cerebellar atrophy with postnatal progressive microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013351

Submitter: Labcorp Genetics (formerly Invitae)

infantile cerebral and cerebellar atrophy with postnatal progressive microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013351

Submitter: G2P

infantile cerebral and cerebellar atrophy with postnatal progressive microcephalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013351

Submitter: Natera

Clinical Genomic Database (CGD)

Microcephaly, postnatal progressive, with seizures and brain atrophyAR

Manifestation: Neurologic

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: 20950787

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MED17 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 530

Infantile cerebral and cerebellar atrophy with postnatal progressive microcephalyTotal: 148

Inborn genetic diseasesTotal: 87

not specifiedTotal: 37

MED17-related disorderTotal: 13

Intellectual disabilityTotal: 2

MED17-related disordersTotal: 2

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004268.5. 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			8 clinvar	228 clinvar	7 clinvar	243
missense		3 clinvar	175 clinvar	13 clinvar		191
nonsense	15 clinvar	18 clinvar	2 clinvar			35
start loss						0
frameshift	19 clinvar	11 clinvar				30
splice donor/acceptor (+/-2bp)		21 clinvar	1 clinvar			22
Total	34	53	186	241	7	521

Highest pathogenic variant AF is 0.00005392406

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004268.5	RefSeq	NP_004259.3	12	MANE Select
ENST00000251871.9	Ensembl	ENSP00000251871.3	12	MANE Select
ENST00000528786.2	Ensembl	ENSP00000433626.2	2	Standard
ENST00000533133.6	Ensembl	ENSP00000433090.2	10	Standard

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
positive regulation of transcription, DNA-templated

Molecular Function

transcription coregulator activity
transcription coactivator activity
protein binding
nuclear receptor transcription coactivator activity
signaling receptor activity

Cellular Component

nucleus
nucleoplasm
transcription factor complex
membrane
mediator complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000251871
Coding exons: 12
Length: 30469
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125747
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.878	298	344	0.867	0.0000172	4263
Missense (PolyPhen)		71	90.435	0.7851		1127
Synonymous	0.598	116	124	0.932	0.00000613	1218
Loss of Function	2.63	20	37.3	0.536	0.00000208	395

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00029	0.00028	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

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: 0.131

Intolerance Scores

LoFtool: 0.864
RVIS EVS: -0.78
RVIS percentile EVS: 12.88

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.768

Gene Damage Prediction

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