THRA

protein-coding

thyroid hormone receptor alpha, the group of Thyroid hormone receptors

Gene summary

The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

Previous symbols:

THRA1
THRA2
ERBA1

MANE transcript

NM_199334.5

Inheritance

ClinVar variants

P:17U:53B:17

Top phenotype

Hypothyroidism, congenital, nongoitrous, 6

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr17:40,058,290-40,093,867

External References & Databases

Ensembl (ENSG00000126351)

Transcript & Mutation Effects

hg38 • Region Span ~35.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital nongoitrous hypothyroidism 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013757

Submitter: PanelApp Australia

congenital nongoitrous hypothyroidism 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013757

Submitter: Labcorp Genetics (formerly Invitae)

congenital nongoitrous hypothyroidism 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013757

Submitter: G2P

Clinical Genomic Database (CGD)

Hypothyroidism, congenital, nongoitrous, 6AD

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Thyroid replacement therapy has been reported as beneficial in some described individuals

Refs: 22168587; 25670821

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THRA variants in ClinVar

7 Conditions Cataloged

not providedTotal: 40

Inborn genetic diseasesTotal: 19

Congenital nongoitrous hypothyroidism 6Total: 16

not specifiedTotal: 10

THRA-related disorderTotal: 5

Neurodevelopmental disorderTotal: 2

Paediatric disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_199334.5. 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			2 clinvar	12 clinvar	1 clinvar	15
missense	6 clinvar	7 clinvar	39 clinvar	2 clinvar	1 clinvar	55
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift	2 clinvar	1 clinvar	4 clinvar			7
splice donor/acceptor (+/-2bp)			6 clinvar	1 clinvar		7
Total	9	8	53	15	2	87

Highest pathogenic variant AF is 0.000003420286

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_199334.5	RefSeq	NP_955366.1	8	MANE Select
ENST00000450525.7	Ensembl	ENSP00000395641.3	8	MANE Select
NM_001190918.2	RefSeq	NP_001177847.1	9	Standard
NM_001190919.2	RefSeq	NP_001177848.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
thraa	Danio rerio	Structure: ventricular system Quality: hydrocephalic abnormal

Gene / Model

Organism

Observed Phenotype

thraa

Danio rerio

Structure: ventricular system

Quality: hydrocephalic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
NHR
Nuclear Receptors
Angiopoietin Like Protein 8 Regulatory Pathway

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

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

Cellular Component

nucleus
nucleoplasm
cytosol
RNA polymerase II transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264637
Coding exons: 9
Length: 35578
Individuals with no LoFs: 125691
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125740
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.47	146	321	0.455	0.0000218	3205
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.0012	0.0012	notable
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00018	0.00017	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.594

Intolerance Scores

LoFtool: 0.0245
RVIS EVS: -0.56
RVIS percentile EVS: 19.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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