ACKR4

protein-coding

atypical chemokine receptor 4, the group of Atypical chemokine receptors

Gene summary

The protein encoded by this gene is a member of the G protein-coupled receptor family, and is a receptor for C-C type chemokines. This receptor has been shown to bind dendritic cell- and T cell-activated chemokines including CCL19/ELC, CCL21/SLC, and CCL25/TECK. A pseudogene of this gene is found on chromosome 6. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2013]

Previous symbols:

CCRL1

MANE transcript

NM_016557.4

Inheritance

—

ClinVar variants

U:4B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.19

Max pathogenic AF

—

Genomic locus

chr3:132,597,270-132,618,967

External References & Databases

Ensembl (ENSG00000129048)

Transcript & Mutation Effects

hg38 • Region Span ~21.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACKR4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 4

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016557.4. 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		1
missense			4 clinvar			4
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	4	1	0	5

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016557.4	RefSeq	NP_057641.1	1	MANE Select
ENST00000249887.3	Ensembl	ENSP00000249887.2	1	MANE Select
NM_178445.2	RefSeq	NP_848540.1	1	Standard
ENST00000509820.1	Ensembl	ENSP00000425557.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GPCRs, Class A Rhodopsin-like
Signaling by GPCR
Signal Transduction
Chemokine receptors bind chemokines
Peptide ligand-binding receptors

Biological Process

receptor-mediated endocytosis
chemotaxis
immune response
G protein-coupled receptor signaling pathway
positive regulation of cytosolic calcium ion concentration

Molecular Function

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

Cellular Component

early endosome
plasma membrane
integral component of plasma membrane
external side of plasma membrane
recycling endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000249887
Coding exons: 1
Length: 21731
Individuals with no LoFs: 125433
Homozygous LoFs: 1
Heterozygous LoFs: 140
Defined: 125574
p: 0.000562

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.844	147	179	0.822	0.00000851	2275
Missense (PolyPhen)		45	57.851	0.77786		761
Synonymous	0.0455	61	61.5	0.993	0.00000285	669
Loss of Function	-0.551	12	10.1	1.19	5.75e-7	131

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0.0014	0.0014	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00041	0.00041	rare
South Asian	0.0011	0.0011	notable
Other	0.00049	0.00049	rare

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 CCL2, CCL8, CCL13, CCL19, CCL21 and CCL25. Chemokine-binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization. Plays an important role in controlling the migration of immune and cancer cells that express chemokine receptors CCR7 and CCR9, by reducing the availability of CCL19, CCL21, and CCL25 through internalization. Negatively regulates CXCR3-induced chemotaxis. Regulates T-cell development in the thymus. {ECO:0000269|PubMed:10706668, ECO:0000269|PubMed:23121557, ECO:0000269|PubMed:23341447}.;

Recessive Scores

pRec: 0.0861

Intolerance Scores

RVIS EVS: 0.53
RVIS percentile EVS: 80.73

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