THRA

thyroid hormone receptor alpha, the group of Thyroid hormone receptors

Basic information

Region (hg38): 17:40058290-40093867

Previous symbols: [ "THRA1", "THRA2", "ERBA1" ]

Links

ENSG00000126351 ∙ NCBI:7067 ∙ OMIM:190120 ∙ HGNC:11796 ∙ Uniprot:P10827 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital nongoitrous hypothyroidism 6 (Definitive), mode of inheritance: AD
• congenital nongoitrous hypothyroidism 6 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypothyroidism, congenital, nongoitrous, 6	AD	Endocrine	Thyroid replacement therapy has been reported as beneficial in some described individuals	Endocrine	22168587; 25670821

ClinVar

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

• not_provided (39 variants)
• Inborn_genetic_diseases (16 variants)
• Congenital_nongoitrous_hypothyroidism_6 (13 variants)
• not_specified (9 variants)
• THRA-related_disorder (5 variants)
• Neurodevelopmental_disorder (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the THRA gene is commonly pathogenic or not. These statistics are base on transcript: NM_000199334.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				10	2	12
missense	7	7	29	2	1	46
nonsense	1		2			3
start loss						0
frameshift	2	1	1			4
splice donor/acceptor (+/-2bp)			2	1		3
Total	10	8	34	13	3

Highest pathogenic variant AF is 0.000003420286

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
THRA	protein_coding	protein_coding	ENST00000264637	9	35578

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.327	0.672	125691	0	49	125740	0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.47	146	321	0.455	0.0000218	3205
Missense in Polyphen		38	129.68	0.29303		1231
Synonymous	1.69	109	134	0.814	0.00000969	962
Loss of Function	3.64	6	26.1	0.230	0.00000155	268

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000480	0.000478
Ashkenazi Jewish	0.00119	0.00119
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000177	0.000167
Middle Eastern	0.000163	0.000163
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Isoform Alpha-1: Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine. {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:19926848}.
• Disease: DISEASE: Hypothyroidism, congenital, non-goitrous, 6 (CHNG6) [MIM:614450]: A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance. {ECO:0000269|PubMed:22168587, ECO:0000269|PubMed:24969835, ECO:0000269|PubMed:25670821, ECO:0000269|PubMed:26037512}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Thyroid hormone signaling pathway - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);NHR;Nuclear Receptors;Angiopoietin Like Protein 8 Regulatory Pathway;Endochondral Ossification;Gene expression (Transcription);Generic Transcription Pathway;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;RXR and RAR heterodimerization with other nuclear receptor (Consensus)

Recessive Scores

• pRec: 0.594

Intolerance Scores

• loftool: 0.0245
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.31

Haploinsufficiency Scores

• pHI: 0.457
• hipred: Y
• hipred_score: 0.728
• ghis: 0.673

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Thra
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; 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); hematopoietic system 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); reproductive system phenotype; digestive/alimentary 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); hearing/vestibular/ear phenotype; limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; cellular phenotype; renal/urinary system phenotype; skeleton phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: thraa
• Affected structure: ventricular system
• Phenotype tag: abnormal
• Phenotype quality: hydrocephalic

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;cartilage condensation;ossification;thyroid hormone mediated signaling pathway;regulation of thyroid hormone mediated signaling pathway;regulation of transcription by RNA polymerase II;transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;multicellular organism development;brain development;learning or memory;regulation of heart contraction;female courtship behavior;response to cold;hormone-mediated signaling pathway;animal organ morphogenesis;negative regulation of RNA polymerase II transcriptional preinitiation complex assembly;cell differentiation;erythrocyte differentiation;intracellular receptor signaling pathway;thyroid gland development;regulation of myeloid cell apoptotic process;response to lipid;steroid hormone mediated signaling pathway;negative regulation of transcription, DNA-templated;positive regulation of female receptivity;positive regulation of transcription by RNA polymerase II;regulation of lipid catabolic process;type I pneumocyte differentiation;positive regulation of cold-induced thermogenesis;negative regulation of DNA-templated transcription, initiation
• Cellular component: nucleus;nucleoplasm;cytosol;RNA polymerase II transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;steroid hormone receptor activity;nuclear receptor activity;protein binding;transcription factor binding;zinc ion binding;TBP-class protein binding;protein domain specific binding;nuclear receptor transcription coactivator activity;chromatin DNA binding;signaling receptor activity;transcription regulatory region DNA binding;protein-containing complex binding;thyroid hormone binding