TG

thyroglobulin

Basic information

Region (hg38): 8:132866957-133134903

Links

ENSG00000042832 ∙ NCBI:7038 ∙ OMIM:188450 ∙ HGNC:11764 ∙ Uniprot:P01266 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thyroid dyshormonogenesis 3 (Strong), mode of inheritance: AR
• familial thyroid dyshormonogenesis (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thyroid dyshormonogenesis 3	AR	Endocrine; Oncologic	Medical treatment of hypothyroidism (eg, with T4) can be effective ; Thyroid neoplasms have also been reported, and surveillance may be beneficial to allow early treatment	Endocrine; Oncologic	2584351; 1752952; 14657345; 14557492; 14764776; 16187918; 16403815; 16720658; 16477365; 17244789

ClinVar

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

• not provided (551 variants)
• Iodotyrosyl coupling defect (310 variants)
• Inborn genetic diseases (148 variants)
• not specified (42 variants)
• Iodotyrosyl coupling defect;Autoimmune thyroid disease, susceptibility to, 3 (11 variants)
• TG-related condition (10 variants)
• Autoimmune thyroid disease, susceptibility to, 3;Iodotyrosyl coupling defect (9 variants)
• Congenital hypothyroidism (6 variants)
• Autoimmune thyroid disease, susceptibility to, 3 (5 variants)
• TG-Related Disorders (3 variants)
• Thyroid dyshormonogenesis (2 variants)
• Premature ovarian failure (1 variants)
• Hypothyroidism (1 variants)
• Hereditary breast ovarian cancer syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TG 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			20	185	13	218
missense	2	4	258	28	17	309
nonsense	24	6	2			32
start loss			1			1
frameshift	16	4	1			21
inframe indel			1		1	2
splice donor/acceptor (+/-2bp)	4	6	2			12
splice region		1	8	24	3	36
non coding			21	55	65	141
Total	46	20	306	268	96

Highest pathogenic variant AF is 0.000394

Variants in TG

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

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

Position	Type	Phenotype	Significance	ClinVar
8-132867003-G-T		Iodotyrosyl coupling defect	Uncertain significance (Jan 03, 2022)
8-132867006-C-T			Likely benign (Jun 14, 2023)
8-132867009-G-C			Likely benign (Sep 27, 2023)
8-132867012-C-A			Likely benign (Jan 28, 2024)
8-132867026-C-T		Inborn genetic diseases	Uncertain significance (Dec 18, 2023)
8-132867030-G-A			Likely benign (Sep 06, 2023)
8-132867048-G-A		Iodotyrosyl coupling defect	Pathogenic (May 14, 2020)
8-132867054-G-A			Likely benign (Jan 22, 2024)
8-132867060-T-C			Benign (Jan 24, 2024)
8-132867066-C-T		Iodotyrosyl coupling defect	Uncertain significance (Jan 12, 2018)
8-132867074-T-C			Likely benign (Dec 21, 2023)
8-132867077-G-T			Likely benign (Nov 08, 2023)
8-132867080-G-A			Likely benign (Jul 17, 2023)
8-132867084-T-C			Likely benign (Jan 04, 2024)
8-132867967-G-A			Benign (Nov 12, 2018)
8-132868089-T-C		Iodotyrosyl coupling defect	Benign (Sep 10, 2021)
8-132868109-T-C			Likely benign (Jan 11, 2023)
8-132868111-C-A			Likely benign (May 15, 2023)
8-132868120-C-T			Pathogenic (May 26, 2023)
8-132868125-G-C			Likely benign (Oct 14, 2023)
8-132868130-C-T		not specified	Uncertain significance (Mar 13, 2024)
8-132868132-C-T			Pathogenic/Likely pathogenic (Nov 30, 2023)
8-132868137-C-T			Likely benign (May 22, 2023)
8-132868141-C-T		Iodotyrosyl coupling defect	Uncertain significance (Jan 12, 2018)
8-132868152-G-A		Iodotyrosyl coupling defect	Conflicting classifications of pathogenicity (Dec 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TG	protein_coding	protein_coding	ENST00000220616	48	267945

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.88e-59	0.00133	125260	1	487	125748	0.00194

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.41	1660	1.51e+3	1.10	0.0000914	17985
Missense in Polyphen		421	437.6	0.96207		5199
Synonymous	-1.04	633	601	1.05	0.0000380	5512
Loss of Function	2.62	110	144	0.765	0.00000817	1574

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00458	0.00458
Ashkenazi Jewish	0.00327	0.00328
East Asian	0.00245	0.00245
Finnish	0.00176	0.00176
European (Non-Finnish)	0.00171	0.00170
Middle Eastern	0.00245	0.00245
South Asian	0.00173	0.00173
Other	0.00244	0.00245

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Precursor of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
• Disease: DISEASE: Thyroid dyshormonogenesis 3 (TDH3) [MIM:274700]: A disorder due to thyroid dyshormonogenesis, causing large goiters of elastic and soft consistency in the majority of patients. Although the degree of thyroid dysfunction varies considerably among patients with defective thyroglobulin synthesis, patients usually have a relatively high serum free triiodothyronine (T3) concentration with disproportionately low free tetraiodothyronine (T4) level. The maintenance of relatively high free T3 levels prevents profound tissue hypothyroidism except in brain and pituitary, which are dependent on T4 supply, resulting in neurologic and intellectual defects in some cases. {ECO:0000269|PubMed:10199792, ECO:0000269|PubMed:16477365, ECO:0000269|PubMed:17244789, ECO:0000269|PubMed:17532758, ECO:0000269|PubMed:19509106, ECO:0000269|PubMed:27305979}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoimmune thyroid disease 3 (AITD3) [MIM:608175]: A complex autoimmune disorder comprising two related diseases affecting the thyroid: Graves disease and Hashimoto thyroiditis. In both disorders, thyroid-reactive T-cells are formed and infiltrate the thyroid gland. In Graves disease, the majority of the T-cells undergo a Th2 differentiation and activate B-cells to produce antibodies against the TSH receptor, which stimulate the thyroid and cause clinical hyperthyroidism. In contrast, Hashimoto thyroiditis is characterized by Th1 switching of the thyroid- infiltrating T-cells, which induces apoptosis of thyroid follicular cells and clinical hypothyroidism. {ECO:0000269|PubMed:14657345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Thyroid hormone synthesis - Homo sapiens (human);Autoimmune thyroid disease - Homo sapiens (human);Thyroid hormone synthesis;Thyroxine (Thyroid Hormone) Production (Consensus)

Intolerance Scores

• loftool: 0.858
• rvis_EVS: 1.57
• rvis_percentile_EVS: 95.71

Haploinsufficiency Scores

• pHI: 0.109
• hipred: Y
• hipred_score: 0.546
• ghis: 0.456

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.402

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Tg
• Phenotype: hematopoietic system phenotype; skeleton phenotype; immune system phenotype; 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); digestive/alimentary phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: signal transduction;regulation of signaling receptor activity;iodide transport;thyroid gland development;regulation of myelination;thyroid hormone metabolic process;hormone biosynthetic process
• Cellular component: extracellular region
• Molecular function: hormone activity