AXL

protein-coding

AXL receptor tyrosine kinase, the group of Fibronectin type III domain containing|V-set domain containing|Receptor tyrosine kinases

Gene summary

The protein encoded by this gene is a member of the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase subfamily. The encoded protein possesses an extracellular domain which is composed of two immunoglobulin-like motifs at the N-terminal, followed by two fibronectin type-III motifs. It transduces signals from the extracellular matrix into the cytoplasm by binding to the vitamin K-dependent protein growth arrest-specific 6 (Gas6). This gene may be involved in several cellular functions including growth, migration, aggregation and anti-inflammation in multiple cell types. The encoded protein acts as a host cell receptor for multiple viruses, including Marburg, Ebola and Lassa viruses and is a candidate receptor for the SARS-CoV2 virus. [provided by RefSeq, Sep 2021]

MANE transcript

NM_021913.5

Inheritance

ClinVar variants

P:1U:146B:67

Top phenotype

AXL-related disorder

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr19:41,219,223-41,261,766

External References & Databases

Ensembl (ENSG00000167601)

Transcript & Mutation Effects

hg38 • Region Span ~42.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kallmann syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AXL variants in ClinVar

8 Conditions Cataloged

not providedTotal: 160

not specifiedTotal: 99

AXL-related disorderTotal: 25

Hypogonadotropic hypogonadism 7 with or without anosmiaTotal: 2

AmenorrheaTotal: 2

Congenital hypogonadotropic hypogonadismTotal: 1

NK-cell enteropathyTotal: 1

Genetic non-acquired premature ovarian failureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021913.5. 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			4 clinvar	33 clinvar	12 clinvar	49
missense		1 clinvar	131 clinvar	19 clinvar	3 clinvar	154
nonsense						0
start loss			1 clinvar			1
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	1	146	52	15	214

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021913.5	RefSeq	NP_068713.2	20	MANE Select
ENST00000301178.9	Ensembl	ENSP00000301178.3	20	MANE Select
NM_001278599.2	RefSeq	NP_001265528.1	14	Standard
NM_001699.6	RefSeq	NP_001690.2	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in squamous cell - TarBase
Ebola Virus Pathway on Host
Ebola Virus Pathway on Host

Biological Process

neuron migration
natural killer cell differentiation
positive regulation of cytokine-mediated signaling pathway
blood vessel remodeling
phagocytosis

Molecular Function

virus receptor activity
phosphatidylserine binding
protein tyrosine kinase activity
transmembrane receptor protein tyrosine kinase activity
protein binding

Cellular Component

extracellular space
plasma membrane
integral component of plasma membrane
cell surface
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301178
Coding exons: 20
Length: 42564
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.44	463	559	0.829	0.0000342	5743
Missense (PolyPhen)		176	235.19	0.74833		2456
Synonymous	-0.0157	228	228	1.00	0.0000142	1845
Loss of Function	4.62	13	47.3	0.275	0.00000221	519

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00024	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding growth factor GAS6 and which is thus regulating many physiological processes including cell survival, cell proliferation, migration and differentiation. Ligand binding at the cell surface induces dimerization and autophosphorylation of AXL. Following activation by ligand, ALX binds and induces tyrosine phosphorylation of PI3- kinase subunits PIK3R1, PIK3R2 and PIK3R3; but also GRB2, PLCG1, LCK and PTPN11. Other downstream substrate candidates for AXL are CBL, NCK2, SOCS1 and TNS2. Recruitment of GRB2 and phosphatidylinositol 3 kinase regulatory subunits by AXL leads to the downstream activation of the AKT kinase. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses. Plays also an important role in inhibition of Toll-like receptors (TLRs)-mediated innate immune response. {ECO:0000269|PubMed:10403904, ECO:0000269|PubMed:11484958, ECO:0000269|PubMed:12364394, ECO:0000269|PubMed:12490074, ECO:0000269|PubMed:15507525, ECO:0000269|PubMed:15733062, ECO:0000269|PubMed:1656220, ECO:0000269|PubMed:18840707}.; FUNCTION: (Microbial infection) Acts as a receptor for Ebolavirus, possibly through GAS6 binding to phosphatidyl-serine at the surface of virion envelope. {ECO:0000269|PubMed:22673088}.;
Disease: DISEASE: Note=AXL and its ligand GAS6 are highly expressed in thyroid carcinoma tissues, and might thus be involved in thyroid tumorigenesis. Overexpression of AXL and its ligand was also detected in many other cancers such as myeloproliferative disorders, prostatic carcinoma cells, or breast cancer.;

Recessive Scores

pRec: 0.233

Intolerance Scores

LoFtool: 0.241
RVIS EVS: -0.95
RVIS percentile EVS: 9.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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