ACTG1

protein-coding

actin gamma 1, the group of Actins

Gene summary

Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

Previous symbols:

ACTG
DFNA20
DFNA26

MANE transcript

NM_001614.5

Inheritance

ClinVar variants

P:82U:203B:281

Top phenotype

Baraitser-Winter syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr17:81,509,413-81,523,847

External References & Databases

Ensembl (ENSG00000184009)

Transcript & Mutation Effects

hg38 • Region Span ~14.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 20STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011480

Submitter: PanelApp Australia

Baraitser-winter syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013812

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

Baraitser-Winter cerebrofrontofacial syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017579

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The ACTG1 gene has been reported in cases of autosomal dominant nonsyndromic hearing loss (ADNSHL) DFNA20/26 with or without vestibular involvement and autosomal dominant Baraitser-Winter syndrome (BWS). Per criteria outlined by the ClinGen Lumping and Splitting Working group, while the molecular mechanism is not yet fully understood, individual variants appear to segregate with specific phenotypes and we have therefore split curations for the disease entities BWS and ADNSHL. ACTG1 was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2003 (Zhu et al., PMID: 13680526). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental evidence. MIssense variants in this gene have been reported in at least 24 probands with ADNSHL in 15 publications (Zhu et al., 2003 PMID: 13680526; van Wijk et al., 2003 PMID: 14684684; Rendtorff et al., 2006 PMID: 16773128; Morin et al., 2009 PMID: 19477959; de Heer et al., 2009 PMID: 19548389; Liu et al., 2008 PMID: 18804074; Miyagawa et al., 2013 PMID: 24130743; Miyagawa et al., 2015 PMID: 25792668; Baek et all., 2013 PMID: 22938506; Park et al., 2013 PMID: 23506231; Vona et al., 2014 PMID: 24875298; Wei et al., 2014 PMID: 25388789; Cabanillas et al., 2018 PMID: 29986705; Lee et al., 2018 PMID: 29620237; Wang et al. 2018 PMID: 30599039). Variants in this gene segregated with disease in >100 additional family members. Although most de novo variants are seen in cases of BWS due to reduced reproductive fitness, de novo variants have been observed in individuals with ADNSHL (LMM unpublished data; Cabanillas et al. 2018 PMID: 29986705; Wang et al. 2018 PMID: 29357087). No loss-of-function variants have been reported in affected individuals, and one individual with a large deletion on chromosome 17 encompassing the ACTG1 gene did not have any of the major features of BWS including hearing loss (Riviere et al. 2012 PMID: 22366783). Additionally, no changes in protein levels of ACTG1 in patient cell lines containing pathogenic variants in ACTG1 were observed (Riviere et al. 2012 PMID: 22366783). These data suggest haploinsufficiency is not a mechanism of either ADNSHL or BWS and suggest both disorders may be due to gain-of-function through two distinct effects. Yeast models support functional effects of some of the reported hearing loss-causing variants (Bryan et al. 2006 PMID: 16690605, Bryan et al. 2009 PMID: 19419963; Morin et al., 2009 PMID: 19477959), and there is evidence that the amino acid position 118 is a mutational hot spot (Wang et al. 2018, PMID: 30599039). A homozygous ACTG1-null mouse model demonstrates progressive hearing loss which supports a role of the ACTG1 gene in hearing (Belyantseva et al. 2009, PMID: 19497859); however, this model constributed only limited experimental support given the mismatch in mutational mechanism to the human cases. Perrin et al., 2010 (PMID: 20976199) studied an ACTG1 conditional mouse model, however this model did not contribute additional data beyond the first mouse model given that the gene was knocked out as well. In summary, ACTG1 is definitively associated with autosomal dominant nonsyndromic hearing loss, based primarily on many human case observations with extensive segregation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 01/07/19.

Baraitser-winter syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013812

Submitter: G2P

autosomal dominant nonsyndromic hearing loss 20STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011480

Submitter: Labcorp Genetics (formerly Invitae)

Baraitser-winter syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013812

Submitter: ClinGen

The ACTG1 gene has been reported in both autosomal dominant nonsyndromic hearing loss (ADNSHL) DFNA20/26 with or without vestibular involvement and autosomal dominant Baraitser-Winter syndrome (BWS). Per criteria outlined by the ClinGen Lumping and Splitting Working group, while the molecular mechanism is not yet fully understood, individual variants appear to segregate with specific phenotypes and we have therefore split curations for the disease entities BWS and ADNSHL. The primary features of BWS include intellectual disability, trigonocephaly, hypertelorism, ptosis, and arched eyebrows, and secondary features include pachygyria/lissencephaly, coloboma, hearing loss, epilepsy, microphthalmia, agenesis or thickened corpus callosum (Yates et al. 2017 PMID: 27625340). The ACTG1 and autosomal dominant BWS relationship is supported by at least 11 de novo missense variants reported in at least 12 probands in 5 publications (Riviere et al. 2012 PMID: 22366783; Verloes et al. 2014 PMID: 25052316 ; Rainger et al. 2017 PMID: 28493397; Poirier et al. 2015 PMID: 26188271; Donato et al. 2016 PMID: 27240540). Additional cases have been reported, however parents were either not tested or not available for testing. 62% (8/13) of reported probands with a BWS diagnosis for whom clinical information was available had some degree of hearing loss, though severity, progressivity, and age-of-onset of hearing loss were variable. Variable expressivity has been reported in one family with hearing loss, seizures, estropia, and ocular coloboma (Kemerley et al. 2017 PMID: 27096712), as has isolated coloboma (Rainger et al. 2017 PMID: 28493397). In general, the association of de novo occurence with BWS is likely due to reduced reproductive fitness, however de novo variants have also been observed in individuals with ADNSHL (LMM unpublished data; Cabanillas et al. 2018 PMID: 29986705; Wang et al. 2018 PMID: 29357087). The existence of variant-specific phenotypes are supported by functional evidence in cell lines derived from BWS patients (Riviere et al. 2012 PMID: 22366783) and in yeast containing hearing loss-causing variants (Bryan et al. 2006 PMID: 16690605). No loss-of-function variants have been reported in affected individuals, and one individual with a large deletion on chromosome 17 encompassing the ACTG1 gene did not have any of the major features of BWS (Riviere et al. 2012 PMID: 22366783). Additionally, no changes in protein levels of ACTG1 in patient cell lines containing pathogenic variants in ACTG1 were observed (Riviere et al. 2012 PMID: 22366783). These data suggest haploinsufficiency is not a mechanism of either ADNSHL or BWS and suggest both disorders may be due to gain-of-function through two distinct effects. In summary, ACTG1 is definitively associated with autosomal dominant Baraitser-Winter syndrome, primarily based upon many cases with de novo variation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 01/07/19.

Baraitser-winter syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013812

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Baraitser-Winter syndrome 2AD

Manifestation: Audiologic/Otolaryngologic;Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Though the condition may be recognizable, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Refs: 5654493; 3351890; 12519370; 14684684; 13680526; 16773128; 19477959; 22366783; 25052316

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACTG1 variants in ClinVar

19 Conditions Cataloged

Baraitser-winter syndrome 2Total: 487

Autosomal dominant nonsyndromic hearing loss 20Total: 483

not providedTotal: 295

not specifiedTotal: 186

ACTG1-related disorderTotal: 91

Inborn genetic diseasesTotal: 29

Rare genetic deafnessTotal: 3

LissencephalyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001614.5. 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			9 clinvar	273 clinvar	6 clinvar	288
missense	13 clinvar	69 clinvar	170 clinvar	2 clinvar		254
nonsense			7 clinvar			7
start loss						0
frameshift			9 clinvar			9
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	13	69	203	275	6	566

Highest pathogenic variant AF is 0.0000013682248

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001614.5	RefSeq	NP_001605.1	5	MANE Select
ENST00000573283.7	Ensembl	ENSP00000458435.1	5	MANE Select
NM_001199954.3	RefSeq	NP_001186883.1	5	Standard
ENST00000570382.2	Ensembl	ENSP00000466346.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Oxytocin signaling pathway - Homo sapiens (human)
Salmonella infection - Homo sapiens (human)
Adherens junction - Homo sapiens (human)

Biological Process

retina homeostasis
cell junction assembly
Fc-gamma receptor signaling pathway involved in phagocytosis
sarcomere organization
ephrin receptor signaling pathway

Molecular Function

structural constituent of cytoskeleton
protein binding
profilin binding
ATP binding
ubiquitin protein ligase binding

Cellular Component

extracellular space
nucleus
cytosol
cytoskeleton
actin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000575842
Coding exons: 5
Length: 13877
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125745
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.16	72	197	0.366	0.0000101	2431
Missense (PolyPhen)		49	124.26	0.39435		1569
Synonymous	-19.0	291	78.0	3.73	0.00000434	746
Loss of Function	1.95	6	13.8	0.435	6.16e-7	151

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
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)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. {ECO:0000305|PubMed:29581253}.;
Disease: DISEASE: Deafness, autosomal dominant, 20 (DFNA20) [MIM:604717]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:13680526, ECO:0000269|PubMed:14684684, ECO:0000269|PubMed:16773128, ECO:0000269|PubMed:18804074, ECO:0000269|PubMed:19477959, ECO:0000269|PubMed:22938506, ECO:0000269|PubMed:25388789}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Baraitser-Winter syndrome 2 (BRWS2) [MIM:614583]: A rare developmental disorder characterized by the combination of congenital ptosis, high-arched eyebrows, hypertelorism, ocular colobomata, and a brain malformation consisting of anterior- predominant lissencephaly. Other typical features include postnatal short stature and microcephaly, intellectual disability, seizures, and hearing loss. {ECO:0000269|PubMed:22366783}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in ACTG1 has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea. {ECO:0000269|PubMed:28493397}.;

Intolerance Scores

LoFtool: 0.0321
RVIS EVS: -1.93
RVIS percentile EVS: 1.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

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