TACR3

tachykinin receptor 3, the group of Tachykinin receptors

Basic information

Region (hg38): 4:103586031-103719985

Links

ENSG00000169836 ∙ NCBI:6870 ∙ OMIM:162332 ∙ HGNC:11528 ∙ Uniprot:P29371 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism 7 with or without anosmia (Strong), mode of inheritance: AR
• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 11 with or without anosmia (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism	AR	Endocrine	In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required	Endocrine	19079066; 20301509

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TACR3 gene.

• not provided (2 variants)
• Hypogonadotropic hypogonadism (1 variants)
• Hypogonadotropic hypogonadism 11 with or without anosmia (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TACR3 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			5	17	2	24
missense		2	30	3		35
nonsense	2	3				5
start loss						0
frameshift	1	1				2
inframe indel						0
splice donor/acceptor (+/-2bp)	1	2	1			4
splice region						0
non coding			12	15	10	37
Total	4	8	48	35	12

Highest pathogenic variant AF is 0.000375

Variants in TACR3

This is a list of pathogenic ClinVar variants found in the TACR3 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-103589412-A-G			Likely benign (May 10, 2019)
4-103589480-C-G		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 12, 2018)
4-103589504-CAT-C		Isolated GnRH Deficiency	Uncertain significance (Jun 14, 2016)
4-103589539-C-T		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 13, 2018)
4-103589544-C-T		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 12, 2018)
4-103589557-T-C		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 12, 2018)
4-103589588-A-C		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 12, 2018)
4-103589595-A-G		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 12, 2018)
4-103589609-G-A		Hypogonadotropic hypogonadism 11 with or without anosmia	Benign (Jun 26, 2018)
4-103589687-A-G		Inborn genetic diseases	Likely benign (Apr 07, 2022)
4-103589707-T-C			Uncertain significance (May 06, 2022)
4-103589735-C-A		not specified • Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Nov 09, 2023)
4-103589735-C-T		Hypogonadotropic hypogonadism 11 with or without anosmia • TACR3-related disorder	Benign/Likely benign (Dec 27, 2023)
4-103589736-G-A		not specified • Hypogonadotropic hypogonadism 11 with or without anosmia	Benign/Likely benign (May 23, 2023)
4-103589759-G-A		Hypogonadotropic hypogonadism 11 with or without anosmia	Conflicting classifications of pathogenicity (Aug 31, 2023)
4-103589769-A-G		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 12, 2018)
4-103589790-C-T		Hypogonadotropic hypogonadism 11 with or without anosmia	Conflicting classifications of pathogenicity (Apr 13, 2018)
4-103589791-G-A		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Oct 31, 2018)
4-103589791-G-T		Inborn genetic diseases	Uncertain significance (May 07, 2024)
4-103589834-T-A		Hypogonadotropic hypogonadism 11 with or without anosmia • not specified • TACR3-related disorder	Conflicting classifications of pathogenicity (Oct 21, 2024)
4-103589846-C-T		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Oct 11, 2021)
4-103589850-T-A		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 13, 2018)
4-103589855-T-C		Hypogonadotropic hypogonadism 11 with or without anosmia	Conflicting classifications of pathogenicity (Aug 08, 2018)
4-103589874-G-A		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 13, 2018)
4-103589892-C-T		Hypogonadotropic hypogonadism 11 with or without anosmia	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TACR3	protein_coding	protein_coding	ENST00000304883	5	133786

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.81e-17	0.000950	125634	0	114	125748	0.000453

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.577	233	259	0.899	0.0000131	3036
Missense in Polyphen		76	93.857	0.80974		1207
Synonymous	0.0427	98	98.5	0.995	0.00000508	949
Loss of Function	-0.972	23	18.5	1.24	9.57e-7	194

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000512	0.000510
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000491	0.000489
Finnish	0.00	0.00
European (Non-Finnish)	0.000723	0.000721
Middle Eastern	0.000491	0.000489
South Asian	0.000262	0.000261
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: neuromedin-K > substance K > substance P.
• Disease: DISEASE: Hypogonadotropic hypogonadism 11 with or without anosmia (HH11) [MIM:614840]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:19079066, ECO:0000269|PubMed:23643382, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in TACR3 as well as in other HH-associated genes including FGFR1, SPRY4 and KAL1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
• Pathway: Calcium signaling pathway - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Peptide GPCRs;Signaling by GPCR;Signal Transduction;Tachykinin receptors bind tachykinins;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;G alpha (q) signalling events;GPCR downstream signalling (Consensus)

Recessive Scores

• pRec: 0.143

Intolerance Scores

• loftool: 0.791
• rvis_EVS: -0.34
• rvis_percentile_EVS: 30.56

Haploinsufficiency Scores

• pHI: 0.105
• hipred: N
• hipred_score: 0.455
• ghis: 0.436

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.849

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tacr3
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); growth/size/body region phenotype; reproductive system phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: G protein-coupled receptor signaling pathway;tachykinin receptor signaling pathway;aging;positive regulation of heart rate;response to estradiol;regulation of dopamine metabolic process;response to cocaine;hyperosmotic salinity response;response to morphine;positive regulation of blood pressure;regulation of feeding behavior;positive regulation of uterine smooth muscle contraction;positive regulation of flagellated sperm motility
• Cellular component: nucleus;cytoplasm;plasma membrane;integral component of plasma membrane;dendrite membrane;neuronal cell body membrane;sperm midpiece
• Molecular function: tachykinin receptor activity;protein binding