GeneBe

TPO

protein-coding

thyroid peroxidase, the group of Sushi domain containing

Gene summary

This gene encodes a membrane-bound glycoprotein. The encoded protein acts as an enzyme and plays a central role in thyroid gland function. The protein functions in the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Mutations in this gene are associated with several disorders of thyroid hormonogenesis, including congenital hypothyroidism, congenital goiter, and thyroid hormone organification defect IIA. Multiple transcript variants encoding distinct isoforms have been identified for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2011]

MANE transcript

NM_001206744.2

Inheritance

AR

ClinVar variants

P:132U:166B:356

Top phenotype

Thyroid dyshormonogenesis 2A

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr2:1,374,066-1,543,711

External References & Databases

Ensembl (ENSG00000115705)NCBI Gene (7173)OMIM (606765)HGNC:12015GenCCUniProt (P07202)AlphaFoldClinVar (TPO)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~169.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial thyroid dyshormonogenesisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010132

Submitter: Orphanet

thyroid dyshormonogenesis 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010133

Submitter: Labcorp Genetics (formerly Invitae)

thyroid dyshormonogenesis 2ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010133

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Thyroid dyshormonogenesis 2AAR

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: Medical treatment of hypothyroidism (eg, with T4) can be effective; Thyroid neoplasms have also been reported, and surveillance may be beneficial

Refs: 1401057; 8027236; 9814507; 10084596Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPO variants in ClinVar

15 Conditions Cataloged
not providedTotal: 636
Deficiency of iodide peroxidaseTotal: 167
Inborn genetic diseasesTotal: 83
not specifiedTotal: 67
TPO-related disorderTotal: 46
Congenital hypothyroidismTotal: 12
Multiple congenital anomalies/dysmorphic syndrome-intellectual disabilityTotal: 2
Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001206744.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
6
clinvar
318
clinvar
9
clinvar
 334
missense
10
clinvar
27
clinvar
159
clinvar
25
clinvar
2
clinvar
 223
nonsense
17
clinvar
11
clinvar
1
clinvar
 29
start loss
0
frameshift
30
clinvar
16
clinvar
1
clinvar
 47
splice donor/acceptor (+/-2bp)
20
clinvar
1
clinvar
 21
Total577516634511654

Highest pathogenic variant AF is 0.00067094446

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001206744.2RefSeqNP_001193673.116MANE Select
ENST00000329066.9EnsemblENSP00000329869.416MANE Select
NM_000547.6RefSeqNP_000538.316Standard
NM_001206745.2RefSeqNP_001193674.115Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Thyroid hormone synthesis - Homo sapiens (human)
  • Autoimmune thyroid disease - Homo sapiens (human)
  • Tyrosine metabolism - Homo sapiens (human)
  • Thyroid hormone synthesis
  • Thyroxine (Thyroid Hormone) Production

Biological Process

  • thyroid hormone generation
  • response to oxidative stress
  • embryonic hemopoiesis
  • hormone biosynthetic process
  • hydrogen peroxide catabolic process

Molecular Function

  • iodide peroxidase activity
  • peroxidase activity
  • calcium ion binding
  • heme binding

Cellular Component

  • extracellular space
  • plasma membrane
  • integral component of plasma membrane
  • cell surface

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000345913
Coding exons
16
Length
169489
Individuals with no LoFs
125581
Homozygous LoFs
0
Heterozygous LoFs
167
Defined
125748
p
0.000664
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.003355675671.000.00003985971
Missense (PolyPhen)183196.020.933592236
Synonymous-0.8652762581.070.00002131938
Loss of Function0.9803642.90.8390.00000226459

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000990.00098rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish0.00140.0014notable
East Asian0.00190.0019notable
Finnish0.0000460.000046rare
European (Non-Finnish)0.000620.00062rare
South Asian0.000660.00065rare
Other0.000330.00033rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.482

Intolerance Scores

LoFtool
0.854
RVIS EVS
-0.14
RVIS percentile EVS
42.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.764

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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