ACTN4

actinin alpha 4, the group of Actinins

Basic information

Region (hg38): 19:38647648-38731589

Previous symbols: [ "FSGS1" ]

Links

ENSG00000130402 ∙ NCBI:81 ∙ OMIM:604638 ∙ HGNC:166 ∙ Uniprot:O43707 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• focal segmental glomerulosclerosis 1 (Moderate), mode of inheritance: AD
• familial idiopathic steroid-resistant nephrotic syndrome (Supportive), mode of inheritance: AD
• focal segmental glomerulosclerosis 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Focal segmental glomerulosclerosis 1	AD	Renal	The condition can involve renal failure, and early diagnosis may enable management considerations; Renal transplant has been described	Renal	10700177; 15208719; 19142020; 19357256; 19666657

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACTN4 gene.

• not provided (248 variants)
• Focal segmental glomerulosclerosis 1 (86 variants)
• Inborn genetic diseases (27 variants)
• Focal segmental glomerulosclerosis (23 variants)
• not specified (22 variants)
• Kidney disorder (4 variants)
• ACTN4-related condition (2 variants)
• Intellectual disability, autosomal dominant 14 (1 variants)
• Chronic kidney disease (1 variants)
• Nephrotic syndrome (1 variants)
• See cases (1 variants)
• Corticosteroids response (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACTN4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	56	11	69
missense	3	2	70	11	1	87
nonsense						0
start loss						0
frameshift						0
inframe indel	1		3			4
splice donor/acceptor (+/-2bp)			1			1
splice region			9	12	2	23
non coding			10	45	42	97
Total	4	2	86	112	54

Highest pathogenic variant AF is 0.00000657

Variants in ACTN4

This is a list of pathogenic ClinVar variants found in the ACTN4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-38647703-A-G		ACTN4-related disorder	Likely benign (Jul 12, 2019)
19-38647707-G-T		ACTN4-related disorder	Likely benign (Apr 11, 2022)
19-38647758-C-T			Uncertain significance (May 01, 2021)
19-38647770-C-G			Uncertain significance (May 26, 2021)
19-38647800-G-T		Focal segmental glomerulosclerosis 1 • Focal segmental glomerulosclerosis	Uncertain significance (Jan 05, 2024)
19-38647810-C-T		Nephrotic syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 17, 2022)
19-38647819-G-GGGGCAGCAT			Uncertain significance (Jun 15, 2023)
19-38647833-G-A		Inborn genetic diseases	Uncertain significance (Aug 05, 2023)
19-38647906-A-G		Corticosteroids response	drug response (May 20, 2022)
19-38647913-C-T			Benign (Sep 23, 2023)
19-38647919-G-A			Likely benign (Jun 14, 2021)
19-38647923-GC-G			Likely benign (Jan 16, 2022)
19-38647940-G-A			Likely benign (Jul 05, 2018)
19-38647968-T-C		Focal segmental glomerulosclerosis 1	Benign (Dec 05, 2021)
19-38700411-C-T			Likely benign (Jul 10, 2018)
19-38700591-C-T		Focal segmental glomerulosclerosis 1	Conflicting classifications of pathogenicity (May 02, 2023)
19-38700595-C-A			Uncertain significance (Feb 17, 2022)
19-38700602-C-G			Likely benign (Nov 06, 2018)
19-38700607-C-T		Corticosteroids response	Uncertain significance (Jul 21, 2022)
19-38700612-T-C		Focal segmental glomerulosclerosis 1	Likely pathogenic (Sep 20, 2020)
19-38700627-C-G		Focal segmental glomerulosclerosis 1	Uncertain significance (Mar 29, 2020)
19-38700650-C-G			Likely benign (Aug 04, 2023)
19-38700669-T-C		Corticosteroids response	drug response (May 20, 2022)
19-38700673-G-A		Focal segmental glomerulosclerosis 1	Likely pathogenic (Nov 17, 2019)
19-38700677-C-T		Focal segmental glomerulosclerosis 1	Likely benign (Jul 05, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACTN4	protein_coding	protein_coding	ENST00000252699	21	83935

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.40e-7	125729	0	5	125734	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.16	278	553	0.503	0.0000392	6055
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Regulation of actin cytoskeleton - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Leukocyte transendothelial migration - Homo sapiens (human);Arrhythmogenic Right Ventricular Cardiomyopathy;Primary Focal Segmental Glomerulosclerosis FSGS;Focal Adhesion;Striated Muscle Contraction;erk and pi-3 kinase are necessary for collagen binding in corneal epithelia;ucalpain and friends in cell spread;integrin signaling pathway;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;EGFR1;Hemostasis;Nephrin family interactions;Cell-Cell communication;Signaling events mediated by focal adhesion kinase;PDGFR-beta signaling pathway (Consensus)

Recessive Scores

• pRec: 0.729

Intolerance Scores

• loftool: 0.0240
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.78

Haploinsufficiency Scores

• pHI: 0.473
• hipred: Y
• hipred_score: 0.831
• ghis: 0.552

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.874

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Actn4
• Phenotype: renal/urinary system phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); pigmentation phenotype; neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; muscle phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: response to hypoxia;platelet degranulation;protein transport;vesicle transport along actin filament;positive regulation of cell migration;positive regulation of sodium:proton antiporter activity;tumor necrosis factor-mediated signaling pathway;peroxisome proliferator activated receptor signaling pathway;regulation of apoptotic process;retinoic acid receptor signaling pathway;positive regulation of pinocytosis;actin filament bundle assembly;negative regulation of cellular component movement;positive regulation of cellular component movement;bicellular tight junction assembly;negative regulation of substrate adhesion-dependent cell spreading;positive regulation of NIK/NF-kappaB signaling;protein localization to bicellular tight junction;regulation of nucleic acid-templated transcription;positive regulation of nucleic acid-templated transcription
• Cellular component: stress fiber;extracellular region;extracellular space;nucleus;cytoplasm;cytosol;brush border;cell-cell junction;focal adhesion;actin cytoskeleton;nuclear body;Z disc;cortical cytoskeleton;platelet alpha granule lumen;pseudopodium;protein-containing complex;neuron projection;perinuclear region of cytoplasm;extracellular exosome;ribonucleoprotein complex
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;nucleoside binding;transcription coactivator activity;RNA binding;actin binding;integrin binding;calcium ion binding;protein binding;nuclear receptor transcription coactivator activity;chromatin DNA binding;nuclear hormone receptor binding;protein homodimerization activity;retinoic acid receptor binding;ion channel binding;protein N-terminus binding;actin filament binding