NTRK3

protein-coding

neurotrophic receptor tyrosine kinase 3, the group of I-set domain containing|Receptor tyrosine kinases

Gene summary

This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

MANE transcript

NM_001012338.3

Inheritance

ClinVar variants

U:68B:27

Top phenotype

NTRK3-related disorder

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr15:87,859,751-88,256,791

External References & Databases

Ensembl (ENSG00000140538)

Transcript & Mutation Effects

hg38 • Region Span ~397.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*NTRK3* was first reported in relation to autosomal dominant congenital heart disease in 2014 (Werner et al. 2014, PMID:25196463). At least five unique missense variants in five individuals with congenital heart disease were reported in a publication (PMID: 25196463). Evidence disputing this gene-disease relationship includes case-level data. None of the five variants reported were scorable, as four were too frequent on gnomAD (MAF> 0.00001) to cause disease and one had an unaffected carrier mother. This gene-disease relationship is supported by expression data and two mouse models (PMIDs: 19187638, 9405689, 14550777). In summary, the evidence supporting the relationship between *NTRK3* and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *NTRK3* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date February 6th, 2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NTRK3 variants in ClinVar

10 Conditions Cataloged

not specifiedTotal: 58

not providedTotal: 23

NTRK3-related disorderTotal: 19

Entrectinib resistanceTotal: 2

Repotrectinib resistanceTotal: 1

Neonatal cardiomyopathyTotal: 1

Selitrectinib resistanceTotal: 1

Larotrectinib resistanceTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001012338.3. 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			1 clinvar	17 clinvar	6 clinvar	24
missense			62 clinvar	3 clinvar	1 clinvar	66
nonsense			1 clinvar			1
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	0	0	68	20	7	95

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 83 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001012338.3	RefSeq	NP_001012338.1	18	MANE Select
ENST00000629765.3	Ensembl	ENSP00000485864.1	18	MANE Select
NM_001007156.3	RefSeq	NP_001007157.1	14	Standard
NM_001243101.2	RefSeq	NP_001230030.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neurotrophin signaling pathway - Homo sapiens (human)
Central carbon metabolism in cancer - Homo sapiens (human)
Brain-Derived Neurotrophic Factor (BDNF) signaling pathway
Neuronal System
SHP2 signaling

Biological Process

activation of MAPK activity
neuron migration
negative regulation of protein phosphorylation
positive regulation of protein phosphorylation
transmembrane receptor protein tyrosine kinase signaling pathway

Molecular Function

p53 binding
transmembrane receptor protein tyrosine kinase activity
GPI-linked ephrin receptor activity
neurotrophin receptor activity
protein binding

Cellular Component

plasma membrane
integral component of plasma membrane
axon
receptor complex
glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360948
Coding exons: 18
Length: 381770
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.83	375	489	0.767	0.0000293	5547
Missense (PolyPhen)		94	181.59	0.51765		2111
Synonymous	-2.15	229	191	1.20	0.0000119	1622
Loss of Function	5.18	5	40.6	0.123	0.00000202	469

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation. {ECO:0000269|PubMed:25196463}.;
Disease: DISEASE: Note=Defects in NTRK3 are associated with susceptibility to congenital heart defects (CHD). A disease characterized by congenital developmental abnormalities involving structures of the heart. CHD are the most common major birth defects and the leading cause of death from congenital malformations. {ECO:0000269|PubMed:25196463}.;

Recessive Scores

pRec: 0.527

Intolerance Scores

LoFtool: 0.0394
RVIS EVS: -1.99
RVIS percentile EVS: 1.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.963

Gene Damage Prediction

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