TPO

thyroid peroxidase, the group of Sushi domain containing

Basic information

Region (hg38): 2:1374066-1543711

Links

ENSG00000115705 ∙ NCBI:7173 ∙ OMIM:606765 ∙ HGNC:12015 ∙ Uniprot:P07202 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thyroid dyshormonogenesis 2A (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 2A	AR	Endocrine; Oncologic	Medical treatment of hypothyroidism (eg, with T4) can be effective; Thyroid neoplasms have also been reported, and surveillance may be beneficial	Endocrine; Oncologic	1401057; 8027236; 9814507; 10084596

ClinVar

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

• not provided (51 variants)
• Deficiency of iodide peroxidase (17 variants)
• Neurodevelopmental disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TPO 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			1	272	12	285
missense	7	14	81	9	9	120
nonsense	18	1				19
start loss						0
frameshift	26	2	1			29
inframe indel	2	1	1			4
splice donor/acceptor (+/-2bp)		12				12
splice region		1	4	32	2	39
non coding			12	116	38	166
Total	53	30	96	397	59

Highest pathogenic variant AF is 0.000118

Variants in TPO

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

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

Position	Type	Phenotype	Significance	ClinVar
2-1412635-T-C			Uncertain significance (Nov 11, 2022)
2-1413472-A-G		Deficiency of iodide peroxidase	Benign (Jan 12, 2018)
2-1413478-C-T		Deficiency of iodide peroxidase	Uncertain significance (Jan 13, 2018)
2-1413496-C-T		Deficiency of iodide peroxidase	Uncertain significance (Jan 12, 2018)
2-1413537-G-C		Deficiency of iodide peroxidase	Uncertain significance (Apr 27, 2017)
2-1413564-T-C		Deficiency of iodide peroxidase	Uncertain significance (Jan 12, 2018)
2-1414397-G-A		Deficiency of iodide peroxidase	Uncertain significance (Apr 27, 2017)
2-1414416-C-T			Likely benign (Jan 31, 2024)
2-1414417-G-A		Deficiency of iodide peroxidase	Conflicting classifications of pathogenicity (Jan 05, 2024)
2-1414417-G-T			Likely benign (Dec 19, 2023)
2-1414420-C-G		not specified • Deficiency of iodide peroxidase	Benign (Feb 01, 2024)
2-1414420-C-T		Deficiency of iodide peroxidase	Conflicting classifications of pathogenicity (Dec 19, 2023)
2-1414429-G-A			Likely benign (Sep 22, 2023)
2-1414438-G-A		Deficiency of iodide peroxidase • not specified	Conflicting classifications of pathogenicity (Jan 31, 2024)
2-1414439-C-T			Likely benign (Sep 05, 2023)
2-1414438-G-GCTGGTTATGGCCTGCACAGA		Deficiency of iodide peroxidase	Pathogenic (Sep 09, 2023)
2-1414446-T-C		Inborn genetic diseases	Uncertain significance (Jan 09, 2024)
2-1414455-C-A		Inborn genetic diseases	Uncertain significance (Mar 21, 2023)
2-1414455-C-T		Inborn genetic diseases	Uncertain significance (Apr 15, 2024)
2-1414479-C-T		Inborn genetic diseases	Likely benign (May 14, 2024)
2-1414480-G-A			Likely benign (Dec 26, 2023)
2-1414486-G-A			Likely benign (Oct 29, 2023)
2-1414489-A-G			Likely benign (Dec 29, 2023)
2-1414509-A-G			Likely benign (Nov 26, 2023)
2-1414510-G-A			Likely benign (Jul 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TPO	protein_coding	protein_coding	ENST00000345913	16	169489

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.82e-21	0.0210	125581	0	167	125748	0.000664

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.00335	567	567	1.00	0.0000398	5971
Missense in Polyphen		183	196.02	0.93359		2236
Synonymous	-0.865	276	258	1.07	0.0000213	1938
Loss of Function	0.980	36	42.9	0.839	0.00000226	459

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00125	0.00124
Ashkenazi Jewish	0.00139	0.00139
East Asian	0.00191	0.00190
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000617	0.000615
Middle Eastern	0.00191	0.00190
South Asian	0.000657	0.000653
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4). {ECO:0000250|UniProtKB:P09933}.
• Disease: DISEASE: Note=An alternative splicing in the thyroperoxidase mRNA can cause Graves' disease.; DISEASE: Thyroid dyshormonogenesis 2A (TDH2A) [MIM:274500]: A disorder due to defective conversion of accumulated iodide to organically bound iodine. The iodide organification defect can be partial or complete. {ECO:0000269|PubMed:10084596, ECO:0000269|PubMed:10468986, ECO:0000269|PubMed:11061528, ECO:0000269|PubMed:11415848, ECO:0000269|PubMed:11874711, ECO:0000269|PubMed:11916616, ECO:0000269|PubMed:12213873, ECO:0000269|PubMed:12490071, ECO:0000269|PubMed:12843174, ECO:0000269|PubMed:12864797, ECO:0000269|PubMed:12938097, ECO:0000269|PubMed:16284446, ECO:0000269|PubMed:16684826, ECO:0000269|PubMed:27305979, ECO:0000269|PubMed:7550241, ECO:0000269|PubMed:9024270, ECO:0000269|PubMed:9924196}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Thyroid hormone synthesis - Homo sapiens (human);Autoimmune thyroid disease - Homo sapiens (human);Tyrosine metabolism - Homo sapiens (human);Thyroid hormone synthesis;Thyroxine (Thyroid Hormone) Production;Differentiation Pathway;Hematopoietic Stem Cell Differentiation;Development of pulmonary dendritic cells and macrophage subsets;Amino Acid metabolism;Metabolism of amino acids and derivatives;thyroid hormone biosynthesis;Tyrosine metabolism;Androgen and estrogen biosynthesis and metabolism;Purine metabolism;Metabolism;Thyroxine biosynthesis;Amine-derived hormones (Consensus)

Recessive Scores

• pRec: 0.482

Intolerance Scores

• loftool: 0.854
• rvis_EVS: -0.14
• rvis_percentile_EVS: 42.36

Haploinsufficiency Scores

• pHI: 0.186
• hipred: N
• hipred_score: 0.489
• ghis: 0.441

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.764

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tpo
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear 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); hematopoietic system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype

Gene ontology

• Biological process: thyroid hormone generation;response to oxidative stress;embryonic hemopoiesis;hormone biosynthetic process;hydrogen peroxide catabolic process;oxidation-reduction process;cellular oxidant detoxification
• Cellular component: extracellular space;plasma membrane;integral component of plasma membrane;cell surface
• Molecular function: iodide peroxidase activity;peroxidase activity;calcium ion binding;heme binding