GeneBe

STAC3

protein-coding

SH3 and cysteine rich domain 3

Gene summary

The protein encoded by this gene is a component of the excitation-contraction coupling machinery of muscles. This protein is a member of the Stac gene family and contains an N-terminal cysteine-rich domain and two SH3 domains. Mutations in this gene are a cause of Native American myopathy. [provided by RefSeq, Nov 2013]

MANE transcript

NM_145064.3

Inheritance

AR

ClinVar variants

P:18U:130B:57

Top phenotype

Congenital myopathy 13

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr12:57,243,453-57,251,188

External References & Databases

Ensembl (ENSG00000185482)NCBI Gene (246329)OMIM (615521)HGNC:28423GenCCUniProt (Q96MF2)AlphaFoldClinVar (STAC3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~7.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bailey-Bloch congenital myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009722

Submitter: G2P

Bailey-Bloch congenital myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009722

Submitter: Orphanet

Bailey-Bloch congenital myopathyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009722

Submitter: Ambry Genetics

Bailey-Bloch congenital myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009722

Submitter: PanelApp Australia

Bailey-Bloch congenital myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009722

Submitter: ClinGen

STAC3 was first reported in relation to autosomal recessive Bailey-Bloch congenital myopathy in 2013 (Horstick EJ, et al., 2013, PMID: 23736855). At least nine unique variants (e.g. missense, nonsense, frameshift, and intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 20 probands in four publications (PMIDs:28411587, 23736855, 28777491, 30168660). Variants in this gene segregated with disease in eight additional family members. This gene-disease association is supported by its biochemical function in myoblast differentiation (PMID: 24788338), its expression in skeletal muscle (PMID: 23626854), and animal models in both zebrafish (PMID: 23736855) and mice (PMID: 23626854). In summary, STAC3 is definitively associated with autosomal recessive Bailey-Bloch congenital myopathy.

Bailey-Bloch congenital myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009722

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Congenital myopathy 13AR

Manifestation: Craniofacial; Musculoskeletal

Intervention: Musculoskeletal; Pharmacogenomic

Rationale: Among other findings, individuals have been described with susceptibility to malignant hyperthermia related to anesthesia, and awareness may allow preventive measures

Refs: 23736855Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STAC3 variants in ClinVar

6 Conditions Cataloged
Bailey-Bloch congenital myopathyTotal: 240
not providedTotal: 45
Inborn genetic diseasesTotal: 43
not specifiedTotal: 20
STAC3-related disorderTotal: 9
Congenital myopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145064.3. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
52
clinvar
1
clinvar
 55
missense
1
clinvar
119
clinvar
3
clinvar
1
clinvar
 124
nonsense
3
clinvar
2
clinvar
2
clinvar
 7
start loss
0
frameshift
5
clinvar
3
clinvar
1
clinvar
 9
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
6
clinvar
 10
Total99130552205

Highest pathogenic variant AF is 0.000064427644

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_145064.3RefSeqNP_659501.111MANE Select
ENST00000332782.7EnsemblENSP00000329200.211MANE Select
NM_001286256.2RefSeqNP_001273185.110Standard
NM_001286257.2RefSeqNP_001273186.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
stac3Danio rerio

Structure: fast muscle cell

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • skeletal muscle contraction
  • neuromuscular synaptic transmission
  • intracellular signal transduction
  • skeletal muscle fiber development
  • positive regulation of voltage-gated calcium channel activity

Molecular Function

  • protein binding
  • identical protein binding
  • metal ion binding

Cellular Component

  • nucleoplasm
  • cytosol
  • voltage-gated calcium channel complex
  • extrinsic component of cytoplasmic side of plasma membrane
  • sarcolemma

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000332782
Coding exons
11
Length
7741
Individuals with no LoFs
125693
Homozygous LoFs
0
Heterozygous LoFs
55
Defined
125748
p
0.000219
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9061802180.8270.00001222405
Missense (PolyPhen)7684.6920.89737892
Synonymous1.266275.90.8170.00000398652
Loss of Function2.441022.50.4450.00000122256

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000500.00049rare
Latino/Admixed American0.000320.00032rare
Ashkenazi Jewish00.0absent
East Asian0.000330.00033rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000230.00023rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Required for normal excitation-contraction coupling in skeletal muscle and for normal muscle contraction in response to membrane depolarization. Required for normal Ca(2+) release from the sarcplasmic reticulum, which ultimately leads to muscle contraction. Probably functions via its effects on muscle calcium channels (PubMed:23736855, PubMed:29078335). Increases CACNA1S channel activity, in addition to its role in enhancing the expression of CACNA1S at the cell membrane. Has a redundant role in promoting the expression of the calcium channel CACNA1S at the cell membrane (By similarity). Slows down the inactivation rate of the calcium channel CACNA1C (PubMed:29078335). {ECO:0000250|UniProtKB:Q8BZ71, ECO:0000269|PubMed:23736855, ECO:0000269|PubMed:29078335}.;
Disease
DISEASE: Native American myopathy (NAM) [MIM:255995]: A disease characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia provoked by anesthesia. {ECO:0000269|PubMed:23736855, ECO:0000269|PubMed:29078335}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.105

Intolerance Scores

LoFtool
0.420
RVIS EVS
-0.14
RVIS percentile EVS
43.57

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.758

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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