NTRK1
neurotrophic receptor tyrosine kinase 1, the group of Immunoglobulin like domain containing|Receptor tyrosine kinases
Basic information
Region (hg38): 1:156815636-156881850
Links
Phenotypes
GenCC
Source:
- hereditary sensory and autonomic neuropathy type 4 (Definitive), mode of inheritance: AR
- hereditary sensory and autonomic neuropathy type 4 (Supportive), mode of inheritance: AR
- familial medullary thyroid carcinoma (Supportive), mode of inheritance: AD
- hereditary sensory and autonomic neuropathy type 4 (Strong), mode of inheritance: AR
- hereditary sensory and autonomic neuropathy type 4 (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Insensitivity to pain, congenital, with anhidrosis | AR | Allergy/Immunology/Infectious; Dermatologic; Neurologic | Individuals may manifest with poor thermoregulation due to anhidrosis, which may result in potentially severe fevers, and awareness can allow measures to help control temperature in order to decrease potential sequelae; Congenital insensitivity to pain can result in injuries, some of which may in theory be preventable with early diagnosis and preventive measures (eg, tooth extraction may be indicated); Recurrent infections have been described, and preventive measures and awareness allowing early diagnosis and aggressive treatmentment of infections may be beneficial | Allergy/Immunology/Infectious; Dermatologic; Neurologic | 8696348; 10088743; 10861667; 11744315; 12949319; 15534759; 15695606; 16490492; 19618435; 20301726; 19089473; 17915006; 20647579; 21559108; 21708027; 22032467; 22355435; 22653642; 22814739; 22957891; 23112235 |
ClinVar
This is a list of variants' phenotypes submitted to
- Hereditary insensitivity to pain with anhidrosis (95 variants)
- Charcot-Marie-Tooth disease (8 variants)
- not provided (6 variants)
- Inborn genetic diseases (3 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the NTRK1 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 | 403 | 415 | ||||
| missense | 16 | 317 | 23 | 367 | ||
| nonsense | 24 | 28 | ||||
| start loss | 3 | |||||
| frameshift | 49 | 56 | ||||
| inframe indel | 7 | |||||
| splice donor/acceptor (+/-2bp) | 20 | 29 | ||||
| splice region | 2 | 2 | 10 | 63 | 1 | 78 |
| non coding | 193 | 41 | 242 | |||
| Total | 94 | 48 | 335 | 619 | 51 |
Highest pathogenic variant AF is 0.0000394
Variants in NTRK1
This is a list of pathogenic ClinVar variants found in the NTRK1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 1-156815752-AC-A | Benign (Mar 26, 2020) | |||
| 1-156815821-A-G | NTRK1-related disorder | Likely benign (May 19, 2020) | ||
| 1-156815825-G-A | not specified • Hereditary insensitivity to pain with anhidrosis • X-linked lymphoproliferative disease due to SH2D1A deficiency | Benign (Jul 07, 2023) | ||
| 1-156815843-T-C | NTRK1-related disorder | Likely benign (Mar 28, 2024) | ||
| 1-156815941-T-C | Likely benign (Oct 25, 2018) | |||
| 1-156815970-AG-A | Benign (Jun 14, 2018) | |||
| 1-156815979-A-G | Hereditary insensitivity to pain with anhidrosis | Benign (Jul 08, 2021) | ||
| 1-156815987-G-A | Hereditary insensitivity to pain with anhidrosis | Benign (Jul 08, 2021) | ||
| 1-156816018-C-G | Likely benign (Apr 01, 2024) | |||
| 1-156816045-G-A | Likely benign (Jun 01, 2021) | |||
| 1-156840887-C-A | not specified | Uncertain significance (Oct 12, 2022) | ||
| 1-156840910-C-T | not specified | Likely benign (Mar 31, 2023) | ||
| 1-156840962-G-A | not specified | Uncertain significance (Nov 09, 2021) | ||
| 1-156840978-C-T | Likely benign (Mar 01, 2022) | |||
| 1-156841006-A-G | Hereditary insensitivity to pain with anhidrosis | Uncertain significance (May 28, 2019) | ||
| 1-156841016-G-A | not specified | Uncertain significance (Dec 13, 2021) | ||
| 1-156841019-G-T | not specified | Uncertain significance (Nov 09, 2021) | ||
| 1-156841031-T-A | not specified | Uncertain significance (Dec 06, 2022) | ||
| 1-156841048-G-A | not specified | Uncertain significance (Sep 23, 2023) | ||
| 1-156841109-T-C | Benign (Dec 31, 2019) | |||
| 1-156841431-C-T | not specified | Uncertain significance (Nov 10, 2021) | ||
| 1-156841455-C-A | not specified | Uncertain significance (Mar 14, 2023) | ||
| 1-156841518-C-G | not specified | Uncertain significance (Mar 23, 2023) | ||
| 1-156841518-C-T | not specified | Uncertain significance (May 05, 2022) | ||
| 1-156841518-C-CG | Familial medullary thyroid carcinoma | Uncertain significance (Jul 02, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| NTRK1 | protein_coding | protein_coding | ENST00000524377 | 17 | 66211 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.00000196 | 1.00 | 125706 | 0 | 42 | 125748 | 0.000167 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.03 | 419 | 483 | 0.868 | 0.0000316 | 5085 |
| Missense in Polyphen | 138 | 194.19 | 0.71063 | 2028 | ||
| Synonymous | 0.0396 | 211 | 212 | 0.997 | 0.0000145 | 1660 |
| Loss of Function | 3.19 | 16 | 37.0 | 0.433 | 0.00000176 | 394 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000276 | 0.000268 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000707 | 0.000707 |
| Finnish | 0.0000712 | 0.0000462 |
| European (Non-Finnish) | 0.000168 | 0.000167 |
| Middle Eastern | 0.000707 | 0.000707 |
| South Asian | 0.0000327 | 0.0000327 |
| Other | 0.000168 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1850821, PubMed:1849459, PubMed:1281417, PubMed:8325889, PubMed:15488758, PubMed:17196528, PubMed:27445338). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. {ECO:0000250|UniProtKB:P35739, ECO:0000250|UniProtKB:Q3UFB7, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:1849459, ECO:0000269|PubMed:1850821, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}.;
- Disease
- DISEASE: Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]: Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II. {ECO:0000269|PubMed:10090906, ECO:0000269|PubMed:10233776, ECO:0000269|PubMed:10330344, ECO:0000269|PubMed:10567924, ECO:0000269|PubMed:10861667, ECO:0000269|PubMed:10982191, ECO:0000269|PubMed:11159935, ECO:0000269|PubMed:11310631, ECO:0000269|PubMed:18077166, ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:28177573, ECO:0000269|PubMed:28328124, ECO:0000269|PubMed:8696348}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs) (PubMed:2869410, PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 (PubMed:2869410). An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein (PubMed:1532241). {ECO:0000269|PubMed:1532241, ECO:0000269|PubMed:2869410, ECO:0000269|PubMed:7565764}.;
- Pathway
- PI3K-Akt signaling pathway - Homo sapiens (human);Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Transcriptional misregulation in cancer - Homo sapiens (human);Apoptosis - Homo sapiens (human);Thyroid cancer - Homo sapiens (human);Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;MAPK Signaling Pathway;PI3K-Akt Signaling Pathway;Ras Signaling;Activation of TRKA receptors;Signal Transduction;role of erk5 in neuronal survival pathway;trka receptor signaling pathway;NGF-independant TRKA activation;ARMS-mediated activation;Retrograde neurotrophin signalling;p73 transcription factor network;TRKA activation by NGF;Signalling to RAS;Signalling to p38 via RIT and RIN;IL-7 signaling;Frs2-mediated activation;Prolonged ERK activation events;Signalling to ERKs;PLC-gamma1 signalling;Signaling by NTRK1 (TRKA);Signaling by NTRKs;SHP2 signaling;Signalling to STAT3;PI3K/AKT activation;JAK STAT pathway and regulation;NGF;EPO signaling;Signaling by Receptor Tyrosine Kinases;VEGF;Neurotrophic factor-mediated Trk receptor signaling;p75(NTR)-mediated signaling;Trk receptor signaling mediated by PI3K and PLC-gamma
(Consensus)
Recessive Scores
- pRec
- 0.689
Intolerance Scores
- loftool
- 0.0395
- rvis_EVS
- -0.06
- rvis_percentile_EVS
- 48.91
Haploinsufficiency Scores
- pHI
- 0.207
- hipred
- Y
- hipred_score
- 0.683
- ghis
- 0.424
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.697
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Ntrk1
- 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); vision/eye phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal 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; pigmentation phenotype; muscle phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype;
Gene ontology
- Biological process
- activation of MAPKK activity;positive regulation of protein phosphorylation;protein phosphorylation;transmembrane receptor protein tyrosine kinase signaling pathway;nervous system development;axon guidance;aging;learning or memory;circadian rhythm;negative regulation of cell population proliferation;response to radiation;programmed cell death involved in cell development;positive regulation of neuron projection development;positive regulation of phosphatidylinositol 3-kinase signaling;peptidyl-tyrosine phosphorylation;olfactory nerve development;B cell differentiation;response to nutrient levels;peptidyl-tyrosine autophosphorylation;nerve growth factor signaling pathway;mechanoreceptor differentiation;negative regulation of apoptotic process;positive regulation of programmed cell death;regulation of MAPK cascade;positive regulation of MAPK cascade;negative regulation of neuron apoptotic process;positive regulation of GTPase activity;positive regulation of Ras protein signal transduction;protein autophosphorylation;neurotrophin TRK receptor signaling pathway;ephrin receptor signaling pathway;phosphatidylinositol-mediated signaling;sympathetic nervous system development;response to axon injury;detection of temperature stimulus involved in sensory perception of pain;detection of mechanical stimulus involved in sensory perception of pain;positive regulation of NF-kappaB transcription factor activity;response to hydrostatic pressure;response to electrical stimulus;positive regulation of synapse assembly;positive regulation of synaptic transmission, glutamatergic;Sertoli cell development;axonogenesis involved in innervation;behavioral response to formalin induced pain;positive regulation of ERK1 and ERK2 cascade;cellular response to nicotine;cellular response to amyloid-beta;cellular response to nerve growth factor stimulus
- Cellular component
- Golgi membrane;early endosome;late endosome;plasma membrane;integral component of plasma membrane;cell surface;endosome membrane;axon;dendrite;early endosome membrane;late endosome membrane;protein-containing complex;neuronal cell body;receptor complex;recycling endosome
- Molecular function
- protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;GPI-linked ephrin receptor activity;neurotrophin receptor activity;neurotrophin p75 receptor binding;protein binding;ATP binding;nerve growth factor receptor activity;kinase binding;protein homodimerization activity;neurotrophin binding;nerve growth factor binding