MED12

mediator complex subunit 12, the group of Mediator complex

Basic information

Region (hg38): X:71118542-71144103

Previous symbols: [ "TNRC11", "FGS1" ]

Links

ENSG00000184634 ∙ NCBI:9968 ∙ OMIM:300188 ∙ HGNC:11957 ∙ Uniprot:Q93074 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• FG syndrome 1 (Definitive), mode of inheritance: XLR
• X-linked intellectual disability with marfanoid habitus (Definitive), mode of inheritance: XLR
• X-linked intellectual disability with marfanoid habitus (Supportive), mode of inheritance: XL
• FG syndrome 1 (Supportive), mode of inheritance: XL
• blepharophimosis - intellectual disability syndrome, MKB type (Supportive), mode of inheritance: XL
• FG syndrome 1 (Definitive), mode of inheritance: XL
• X-linked intellectual disability with marfanoid habitus (Definitive), mode of inheritance: XL
• blepharophimosis - intellectual disability syndrome, MKB type (Strong), mode of inheritance: XL
• cholestasis-pigmentary retinopathy-cleft palate syndrome (Strong), mode of inheritance: XL
• X-linked intellectual disability with marfanoid habitus (Strong), mode of inheritance: XL
• FG syndrome 1 (Strong), mode of inheritance: XL
• MED12-related intellectual disability syndrome (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lujan-Fryns syndrome; Opitz-Kaveggia syndrome; FG syndrome; Ohdo syndrome, X-linked	XL	General	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	Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic	4365204; 6711603; 3322000; 10405444; 10508979; 17036352; 17334363; 17369503; 18973276; 19938245; 20301719; 20507344; 20981778; 23395478
Aortic root dilatation and ventricular septal defect were reported in one individual and his maternal uncle

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MED12 gene.

• FG syndrome 1 (702 variants)
• not provided (459 variants)
• FG syndrome (341 variants)
• Familial thoracic aortic aneurysm and aortic dissection (260 variants)
• not specified (128 variants)
• Inborn genetic diseases (37 variants)
• Blepharophimosis - intellectual disability syndrome, MKB type (26 variants)
• Uterine leiomyoma (26 variants)
• X-linked intellectual disability with marfanoid habitus (24 variants)
• Cardiovascular phenotype (18 variants)
• MED12-related condition (17 variants)
• History of neurodevelopmental disorder (17 variants)
• Cholestasis-pigmentary retinopathy-cleft palate syndrome (9 variants)
• Intellectual disability (8 variants)
• MED12-related intellectual disability syndrome (7 variants)
• See cases (4 variants)
• FG syndrome 1;Blepharophimosis - intellectual disability syndrome, MKB type;X-linked intellectual disability with marfanoid habitus (4 variants)
• Blepharophimosis - intellectual disability syndrome, MKB type;FG syndrome 1;X-linked intellectual disability with marfanoid habitus (4 variants)
• X-linked intellectual disability with marfanoid habitus;Blepharophimosis - intellectual disability syndrome, MKB type;FG syndrome 1 (3 variants)
• X-linked intellectual disability with marfanoid habitus;Blepharophimosis - intellectual disability syndrome, MKB type;FG syndrome 1;Cholestasis-pigmentary retinopathy-cleft palate syndrome (2 variants)
• FG syndrome 1;X-linked intellectual disability with marfanoid habitus;Blepharophimosis - intellectual disability syndrome, MKB type (2 variants)
• X-linked intellectual disability with marfanoid habitus;FG syndrome 1;Cholestasis-pigmentary retinopathy-cleft palate syndrome;Blepharophimosis - intellectual disability syndrome, MKB type (2 variants)
• 7 conditions (1 variants)
• Neurodevelopmental delay (1 variants)
• Ehlers-Danlos syndrome, classic type (1 variants)
• Cholestasis-pigmentary retinopathy-cleft palate syndrome;Blepharophimosis - intellectual disability syndrome, MKB type;X-linked intellectual disability with marfanoid habitus;FG syndrome 1 (1 variants)
• MED12-related disorder (1 variants)
• FG syndrome 1;X-linked intellectual disability with marfanoid habitus;Cholestasis-pigmentary retinopathy-cleft palate syndrome;Blepharophimosis - intellectual disability syndrome, MKB type (1 variants)
• Wilms tumor 1;Simpson-Golabi-Behmel syndrome type 1 (1 variants)
• X-linked MED12-related disorder (1 variants)
• MED12-Related Disorders (1 variants)
• Dilated cardiomyopathy 1Y (1 variants)
• X-linked intellectual disability with marfanoid habitus;FG syndrome 1;Blepharophimosis - intellectual disability syndrome, MKB type;Cholestasis-pigmentary retinopathy-cleft palate syndrome (1 variants)
• Blepharophimosis - intellectual disability syndrome, MKB type;X-linked intellectual disability with marfanoid habitus;FG syndrome 1;Cholestasis-pigmentary retinopathy-cleft palate syndrome (1 variants)
• 6 conditions (1 variants)
• Blepharophimosis - intellectual disability syndrome, MKB type;X-linked intellectual disability with marfanoid habitus;Cholestasis-pigmentary retinopathy-cleft palate syndrome;FG syndrome 1 (1 variants)
• FG syndrome;MED12-related intellectual disability syndrome;X-linked intellectual disability with marfanoid habitus (1 variants)
• Cholestasis-pigmentary retinopathy-cleft palate syndrome;FG syndrome 1;X-linked intellectual disability with marfanoid habitus;Blepharophimosis - intellectual disability syndrome, MKB type (1 variants)
• FG syndrome;X-linked intellectual disability with marfanoid habitus;Blepharophimosis - intellectual disability syndrome, MKB type (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MED12 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			12	334	33	379
missense	4	24	461	53	18	560
nonsense	8	3				11
start loss						0
frameshift	3	6				9
inframe indel			32	11	1	44
splice donor/acceptor (+/-2bp)		7	1			8
splice region		1	45	44	3	93
non coding			18	163	77	258
Total	15	40	524	561	129

Variants in MED12

This is a list of pathogenic ClinVar variants found in the MED12 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-71118549-A-G			Benign (Jun 14, 2018)
X-71118708-A-T		not specified	Likely benign (Feb 13, 2018)
X-71118727-G-T		not specified	Likely benign (Mar 17, 2017)
X-71118759-C-T		MED12-related disorder	Uncertain significance (Jun 30, 2023)
X-71118760-G-T		FG syndrome • Familial thoracic aortic aneurysm and aortic dissection	Likely benign (Feb 24, 2024)
X-71118768-G-C		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Feb 01, 2024)
X-71118769-G-C		FG syndrome	Likely benign (Jul 31, 2023)
X-71118781-C-T		not specified • Familial thoracic aortic aneurysm and aortic dissection • FG syndrome	Likely benign (Nov 17, 2023)
X-71118787-C-A		FG syndrome • not specified	Uncertain significance (Jan 29, 2024)
X-71118787-C-T		FG syndrome	Likely benign (Jun 27, 2022)
X-71118788-C-T			Uncertain significance (Sep 20, 2023)
X-71118791-C-T		FG syndrome	Uncertain significance (Jun 06, 2023)
X-71118800-C-A		Familial thoracic aortic aneurysm and aortic dissection • FG syndrome	Likely benign (Nov 02, 2023)
X-71118814-G-A		FG syndrome	Likely benign (Jan 12, 2023)
X-71118820-C-A		FG syndrome	Uncertain significance (Feb 10, 2020)
X-71118824-G-A		FG syndrome	Uncertain significance (Sep 20, 2020)
X-71118824-G-T			Uncertain significance (Jan 13, 2021)
X-71118830-C-G		FG syndrome	Uncertain significance (Oct 09, 2020)
X-71118832-T-C		MED12-related disorder	Likely benign (Aug 31, 2021)
X-71118836-G-A		FG syndrome	Likely benign (Jan 08, 2024)
X-71118839-C-A		FG syndrome	Uncertain significance (Aug 03, 2023)
X-71118843-A-G		FG syndrome	Uncertain significance (Dec 04, 2023)
X-71118847-G-C			Likely pathogenic (Mar 10, 2016)
X-71118850-G-A		FG syndrome	Likely benign (Mar 18, 2022)
X-71118853-G-A		FG syndrome	Uncertain significance (Nov 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MED12	protein_coding	protein_coding	ENST00000374080	45	23898

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.91e-13	121517	1	0	121518	0.00000411

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.58	343	898	0.382	0.0000742	14199
Missense in Polyphen		66	275	0.24		4257
Synonymous	1.25	314	343	0.914	0.0000269	4324
Loss of Function	8.53	2	88.7	0.0226	0.00000676	1318

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000127	0.00000916
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway. {ECO:0000269|PubMed:16565090, ECO:0000269|PubMed:16595664, ECO:0000269|PubMed:17000779}.
• Disease: DISEASE: Lujan-Fryns syndrome (LUJFRYS) [MIM:309520]: Clinically, Lujan-Fryns syndrome can be distinguished from Opitz-Kaveggia syndrome by tall stature, hypernasal voice, hyperextensible digits and high nasal root. {ECO:0000269|PubMed:17369503}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ohdo syndrome, X-linked (OHDOX) [MIM:300895]: A syndrome characterized by mental retardation, feeding problems, and distinctive facial appearance with coarse facial features, severe blepharophimosis, ptosis, a bulbous nose, micrognathia and a small mouth. Dental hypoplasia and deafness can be considered as common manifestations of the syndrome. Male patients show cryptorchidism and scrotal hypoplasia. {ECO:0000269|PubMed:23395478}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Thyroid hormone signaling pathway - Homo sapiens (human);WNT-Ncore;Developmental Biology;Gene expression (Transcription);Generic Transcription Pathway;Hedgehog;RNA Polymerase II Transcription;Transcriptional regulation of white adipocyte differentiation;Regulation of nuclear beta catenin signaling and target gene transcription (Consensus)

Recessive Scores

• pRec: 0.306

Intolerance Scores

• rvis_EVS: -1
• rvis_percentile_EVS: 8.47

Haploinsufficiency Scores

• pHI: 0.462
• hipred: Y
• hipred_score: 0.673
• ghis: 0.581

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.952

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Med12
• Phenotype: growth/size/body region phenotype; craniofacial phenotype; cellular phenotype; skeleton phenotype; embryo phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: med12
• Affected structure: neutrophil
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: neural tube closure;regulation of transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;endoderm development;heart development;oligodendrocyte development;Schwann cell development;protein ubiquitination;stem cell population maintenance;spinal cord development;negative regulation of Wnt signaling pathway;intracellular steroid hormone receptor signaling pathway;androgen receptor signaling pathway;post-anal tail morphogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;embryonic neurocranium morphogenesis;canonical Wnt signaling pathway;Wnt signaling pathway, planar cell polarity pathway;axis elongation involved in somitogenesis;embryonic brain development
• Cellular component: ubiquitin ligase complex;nucleus;nucleoplasm;membrane;mediator complex
• Molecular function: RNA polymerase II distal enhancer sequence-specific DNA binding;chromatin binding;transcription coregulator activity;transcription coactivator activity;protein binding;beta-catenin binding;protein C-terminus binding;protein domain specific binding;nuclear receptor transcription coactivator activity;signaling receptor activity;vitamin D receptor binding;thyroid hormone receptor binding;ubiquitin protein ligase activity