ACKR3

protein-coding

atypical chemokine receptor 3, the group of Atypical chemokine receptors

Gene summary

This gene encodes a member of the G-protein coupled receptor family. Although this protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP), it is now considered to be an orphan receptor, in that its endogenous ligand has not been identified. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. [provided by RefSeq, Jul 2008]

Previous symbols:

CMKOR1
CXCR7

MANE transcript

NM_020311.3

Inheritance

ClinVar variants

P:1U:35B:9

Top phenotype

Oculomotor-abducens synkinesis

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr2:236,567,787-236,582,354

External References & Databases

Ensembl (ENSG00000144476)

Transcript & Mutation Effects

hg38 • Region Span ~14.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

oculomotor-abducens synkinesisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030976

Submitter: PanelApp Australia

oculomotor-abducens synkinesisLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030976

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Oculomotor-abducens synkinesisAR

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: 30372748

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACKR3 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 39

not providedTotal: 5

Premature ovarian failureTotal: 1

Congenital long QT syndromeTotal: 1

Oculomotor-abducens synkinesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020311.3. 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	2 clinvar	3
missense	1 clinvar		35 clinvar	5 clinvar	1 clinvar	42
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	35	6	3	45

Highest pathogenic variant AF is 0.0000013682175

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020311.3	RefSeq	NP_064707.1	1	MANE Select
ENST00000272928.4	Ensembl	ENSP00000272928.3	1	MANE Select
ENST00000447924.1	Ensembl	ENSP00000405945.1	1	Standard
ENST00000929731.1	Ensembl	ENSP00000599790.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ackr3a	Danio rerio	Structure: posterior lateral line neuromast primordium migration Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

ackr3a

Danio rerio

Structure: posterior lateral line neuromast primordium migration

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytokine-cytokine receptor interaction - Homo sapiens (human)
Glucocorticoid Receptor Pathway
Nuclear Receptors Meta-Pathway
Myometrial Relaxation and Contraction Pathways
VEGFA-VEGFR2 Signaling Pathway

Biological Process

angiogenesis
vasculogenesis
chemotaxis
immune response
cell adhesion

Molecular Function

scavenger receptor activity
protein binding
coreceptor activity
C-C chemokine receptor activity
C-X-C chemokine receptor activity

Cellular Component

nucleus
endosome
early endosome
plasma membrane
clathrin-coated pit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000272928
Coding exons: 1
Length: 14572
Individuals with no LoFs: 125746
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125748
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.946	180	219	0.820	0.0000146	2390
Missense (PolyPhen)		36	67.634	0.53228		855
Synonymous	-0.312	107	103	1.04	0.00000803	733
Loss of Function	2.20	2	9.23	0.217	4.06e-7	103

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)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CXCL11 and CXCL12/SDF1. Chemokine binding does not activate G-protein- mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization and activation of MAPK signaling pathway. Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness. In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival. Not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitors but activated by CXCL11 in malignant hemapoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) and enhanced cell adhesion and migration. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development. Acts as coreceptor with CXCR4 for a restricted number of HIV isolates. {ECO:0000269|PubMed:16107333, ECO:0000269|PubMed:16940167, ECO:0000269|PubMed:17804806, ECO:0000269|PubMed:18653785, ECO:0000269|PubMed:19255243, ECO:0000269|PubMed:19380869, ECO:0000269|PubMed:19641136, ECO:0000269|PubMed:20018651, ECO:0000269|PubMed:20161793, ECO:0000269|PubMed:20388803, ECO:0000269|PubMed:20887389, ECO:0000269|PubMed:22300987}.;

Recessive Scores

pRec: 0.183

Intolerance Scores

RVIS EVS: 0.04
RVIS percentile EVS: 57.31

Essentials

Essential (CRISPR): N
Essential (gene trap): N

Gene Damage Prediction

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