ARPC4

protein-coding

actin related protein 2/3 complex subunit 4, the group of Actin related protein 2/3 complex subunits

Gene summary

This gene encodes one of seven subunits of the human Arp2/3 protein complex. This complex controls actin polymerization in cells and has been conserved throughout eukaryotic evolution. This gene encodes the p20 subunit, which is necessary for actin nucleation and high-affinity binding to F-actin. Alternative splicing results in multiple transcript variants. Naturally occurring read-through transcription exists between this gene and the downstream tubulin tyrosine ligase-like family, member 3 (TTLL3), which results in the production of a fusion protein. [provided by RefSeq, Nov 2010]

MANE transcript

NM_005718.5

Inheritance

ClinVar variants

P:2U:16B:2

Top phenotype

Developmental delay, language impairment, and ocular abnormalities

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr3:9,792,495-9,807,101

External References & Databases

Ensembl (ENSG00000241553)

Transcript & Mutation Effects

hg38 • Region Span ~14.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, language impairment, and ocular abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859324

Submitter: G2P

developmental delay, language impairment, and ocular abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859324

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay, language impairment, and ocular abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859324

Submitter: PanelApp Australia

developmental delay, language impairment, and ocular abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859324

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Developmental delay, language impairment, and ocular abnormalitiesAD

Manifestation: Craniofacial; Neurologic; Ophthalmologic

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: 35047857

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARPC4 variants in ClinVar

4 Conditions Cataloged

Inborn genetic diseasesTotal: 16

not providedTotal: 12

not specifiedTotal: 6

Developmental delay, language impairment, and ocular abnormalitiesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005718.5. 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				2 clinvar		2
missense	1 clinvar	1 clinvar	14 clinvar			16
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	1	1	16	2	0	20

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005718.5	RefSeq	NP_005709.1	6	MANE Select
ENST00000397261.8	Ensembl	ENSP00000380431.2	6	MANE Select
NM_001024959.3	RefSeq	NP_001020130.1	3	Standard
NM_001024960.3	RefSeq	NP_001020131.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
Endocytosis - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Bacterial invasion of epithelial cells - Homo sapiens (human)

Biological Process

actin filament polymerization
Arp2/3 complex-mediated actin nucleation
Fc-gamma receptor signaling pathway involved in phagocytosis
actin nucleation
ephrin receptor signaling pathway

Molecular Function

structural constituent of cytoskeleton
protein binding
enzyme binding
protein binding, bridging
actin filament binding

Cellular Component

nucleus
cytosol
Arp2/3 protein complex
site of double-strand break
cell projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000433034
Coding exons: 6
Length: 15232
Individuals with no LoFs: 124728
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124729
p: 0.00000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	42	106	0.396	0.00000589	1239
Missense (PolyPhen)		8	51.441	0.15552		589
Synonymous	0.859	31	37.7	0.822	0.00000188	341
Loss of Function	3.11	0	11.3	0.00	7.19e-7	120

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Actin-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:9230079). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:9230079). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947). {ECO:0000269|PubMed:29925947, ECO:0000269|PubMed:9230079}.;

Recessive Scores

pRec: 0.0989

Intolerance Scores

RVIS EVS: 0.15
RVIS percentile EVS: 63.81

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.824

Gene Damage Prediction

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