TPH2

protein-coding

tryptophan hydroxylase 2

Gene summary

This gene encodes a member of the pterin-dependent aromatic acid hydroxylase family. The encoded protein catalyzes the first and rate limiting step in the biosynthesis of serotonin, an important hormone and neurotransmitter. Mutations in this gene may be associated with psychiatric diseases such as bipolar affective disorder and major depression. [provided by RefSeq, Feb 2016]

MANE transcript

NM_173353.4

Inheritance

ClinVar variants

U:49B:4

Top phenotype

Attention deficit-hyperactivity disorder, susceptibility to, 7

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr12:71,938,845-72,186,618

External References & Databases

Ensembl (ENSG00000139287)

Transcript & Mutation Effects

hg38 • Region Span ~247.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

attention deficit-hyperactivity disorder, susceptibility to, 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013076

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Attention deficit-hyperactivity disorder, susceptibility to, 7AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18347598

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPH2 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 30

Tryptophan 5-monooxygenase deficiencyTotal: 20

not providedTotal: 5

Attention deficit-hyperactivity disorder, susceptibility to, 7Total: 5

Major depressive disorderTotal: 3

Unipolar depression, susceptibility toTotal: 1

Bipolar affective disorder, susceptibility toTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173353.4. 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			5 clinvar	1 clinvar	1 clinvar	7
missense			43 clinvar	2 clinvar		45
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	49	3	1	53

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173353.4	RefSeq	NP_775489.2	11	MANE Select
ENST00000333850.4	Ensembl	ENSP00000329093.3	11	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tph2	Danio rerio	Structure: hematopoietic multipotent progenitor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tph2

Danio rerio

Structure: hematopoietic multipotent progenitor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Folate biosynthesis - Homo sapiens (human)
Tryptophan metabolism - Homo sapiens (human)
Serotonergic synapse - Homo sapiens (human)
Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics
Serotonin Transporter Activity

Biological Process

circadian rhythm
aromatic amino acid family metabolic process
response to activity
response to nutrient levels
serotonin biosynthetic process

Molecular Function

tryptophan 5-monooxygenase activity
iron ion binding

Cellular Component

cytosol
neuron projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000333850
Coding exons: 11
Length: 247773
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125747
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.998	214	259	0.826	0.0000144	3207
Missense (PolyPhen)		83	117.85	0.70428		1421
Synonymous	-0.763	105	95.5	1.10	0.00000517	932
Loss of Function	2.16	15	27.1	0.553	0.00000158	323

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Major depressive disorder (MDD) [MIM:608516]: A common psychiatric disorder. It is a complex trait characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning. {ECO:0000269|PubMed:15629698}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Attention deficit-hyperactivity disorder 7 (ADHD7) [MIM:613003]: A neurobehavioral developmental disorder primarily characterized by the coexistence of attentional problems and hyperactivity, with each behavior occurring infrequently alone. {ECO:0000269|PubMed:18347598}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Naturally occurring variants of TPH2 with impaired enzyme activity could cause deficiency of serotonin production and result in an increased risk of developing behavioral disorders.;

Intolerance Scores

LoFtool: 0.130
RVIS EVS: -0.07
RVIS percentile EVS: 48.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.956

Gene Damage Prediction

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