ACTN4

protein-coding

actinin alpha 4, the group of Actinins

Gene summary

Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

Previous symbols:

FSGS1

MANE transcript

NM_004924.6

Inheritance

ClinVar variants

P:18U:235B:146

Top phenotype

Focal segmental glomerulosclerosis 1

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr19:38,647,649-38,731,589

External References & Databases

Ensembl (ENSG00000130402)

Transcript & Mutation Effects

hg38 • Region Span ~83.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

focal segmental glomerulosclerosis 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011303

Submitter: Labcorp Genetics (formerly Invitae)

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

focal segmental glomerulosclerosis 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011303

Submitter: Ambry Genetics

focal segmental glomerulosclerosis 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011303

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Focal segmental glomerulosclerosis 1AD

Manifestation: Renal

Intervention: Renal

Rationale: The condition can involve renal failure, and early diagnosis may enable management considerations; Renal transplant has been described

Refs: 10700177; 15208719; 19142020; 19357256; 19666657

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACTN4 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 315

Focal segmental glomerulosclerosis 1Total: 176

Inborn genetic diseasesTotal: 77

ACTN4-related disorderTotal: 56

not specifiedTotal: 53

Focal segmental glomerulosclerosisTotal: 23

Corticosteroids responseTotal: 7

Kidney disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004924.6. 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			11 clinvar	109 clinvar	5 clinvar	125
missense	6 clinvar	12 clinvar	201 clinvar	30 clinvar	2 clinvar	251
nonsense			3 clinvar			3
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			19 clinvar			19
Total	6	12	235	139	7	399

Highest pathogenic variant AF is 0.000022947557

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004924.6	RefSeq	NP_004915.2	21	MANE Select
ENST00000252699.7	Ensembl	ENSP00000252699.2	21	MANE Select
NM_001322033.2	RefSeq	NP_001308962.1	21	Standard
NM_001411143.1	RefSeq	NP_001398072.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Focal adhesion - Homo sapiens (human)
Adherens junction - Homo sapiens (human)
Tight junction - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)
Amoebiasis - Homo sapiens (human)

Biological Process

response to hypoxia
platelet degranulation
protein transport
vesicle transport along actin filament
positive regulation of cell migration

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
nucleoside binding
transcription coactivator activity
RNA binding
actin binding

Cellular Component

stress fiber
extracellular region
extracellular space
nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252699
Coding exons: 21
Length: 83935
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125734
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.16	278	553	0.503	0.0000392	6055
Missense (PolyPhen)		129	306.24	0.42123		3260
Synonymous	-1.18	264	241	1.10	0.0000193	1666
Loss of Function	6.30	1	48.1	0.0208	0.00000233	543

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein (Probable). Probably involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation (PubMed:15772161). Involved in tight junction assembly in epithelial cells probably through interaction with MICALL2. Links MICALL2 to the actin cytoskeleton and recruits it to the tight junctions (By similarity). May also function as a transcriptional coactivator, stimulating transcription mediated by the nuclear hormone receptors PPARG and RARA (PubMed:22351778). {ECO:0000250|UniProtKB:P57780, ECO:0000269|PubMed:15772161, ECO:0000269|PubMed:22351778, ECO:0000305|PubMed:9508771}.;
Disease: DISEASE: Focal segmental glomerulosclerosis 1 (FSGS1) [MIM:603278]: A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. {ECO:0000269|PubMed:10700177, ECO:0000269|PubMed:18164029, ECO:0000269|PubMed:18436095, ECO:0000269|PubMed:22351778, ECO:0000269|PubMed:22732337, ECO:0000269|PubMed:23014460, ECO:0000269|PubMed:23890478}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.729

Intolerance Scores

LoFtool: 0.0240
RVIS EVS: -0.71
RVIS percentile EVS: 14.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.874

Gene Damage Prediction

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