SIX1
SIX homeobox 1, the group of SINE class homeoboxes
Basic information
Region (hg38): 14:60643421-60658259
Previous symbols: [ "DFNA23" ]
Links
Phenotypes
GenCC
Source:
- autosomal dominant nonsyndromic hearing loss 23 (Strong), mode of inheritance: AD
- branchiootic syndrome 3 (Strong), mode of inheritance: AD
- branchiootic syndrome 3 (Definitive), mode of inheritance: AD
- autosomal dominant nonsyndromic hearing loss 23 (Definitive), mode of inheritance: AD
- branchio-oto-renal syndrome (Supportive), mode of inheritance: AD
- branchiootic syndrome (Supportive), mode of inheritance: AD
- autosomal dominant nonsyndromic hearing loss (Supportive), mode of inheritance: AD
- branchiootic syndrome 3 (Strong), mode of inheritance: AD
- branchio-oto-renal syndrome (Definitive), mode of inheritance: AD
- branchio-oto-renal syndrome (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Deafness, autosomal dominant 23; Branchiootorenal syndrome 3; Branchiootic syndrome 3 | AD | Audiologic/Otolaryngologic; Renal | Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In BOR, surveillance and treatment/prophylaxis related to vesicoureteral reflux can be beneficial | Audiologic/Otolaryngologic; Craniofacial; Renal | 10777717; 15141091; 16652090; 17637804; 18330911; 20301554 |
| Individuals can have characteristic aural anomalies, but these may not be readily ascertained |
ClinVar
This is a list of variants' phenotypes submitted to
- Branchiootic_syndrome_3 (138 variants)
- Autosomal_dominant_nonsyndromic_hearing_loss_23 (128 variants)
- not_provided (77 variants)
- Inborn_genetic_diseases (22 variants)
- SIX1-related_disorder (10 variants)
- not_specified (8 variants)
- Branchiootorenal_syndrome_1 (7 variants)
- Hearing_impairment (3 variants)
- Nonsyndromic_Hearing_Loss,_Dominant (1 variants)
- Branchiootic_syndrome_1 (1 variants)
- Unilateral_deafness (1 variants)
- Autosomal_dominant_nonsyndromic_hearing_loss (1 variants)
- Branchiootic_syndrome (1 variants)
- Melnick-Fraser_syndrome (1 variants)
- Branchiootorenal_Spectrum_Disorders (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIX1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000005982.4. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 39 | 43 | ||||
| missense | 13 | 105 | 130 | |||
| nonsense | 8 | |||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 11 | |||||
| splice donor/acceptor (+/-2bp) | 1 | |||||
| Total | 9 | 17 | 124 | 45 | 0 |
Highest pathogenic variant AF is 0.00000752498
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| SIX1 | protein_coding | protein_coding | ENST00000247182 | 2 | 14845 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.653 | 0.346 | 125741 | 0 | 6 | 125747 | 0.0000239 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.19 | 119 | 162 | 0.736 | 0.00000718 | 1828 |
| Missense in Polyphen | 11 | 44.919 | 0.24488 | 517 | ||
| Synonymous | -0.905 | 85 | 75.0 | 1.13 | 0.00000352 | 589 |
| Loss of Function | 2.69 | 2 | 12.1 | 0.166 | 5.29e-7 | 119 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.0000994 | 0.0000992 |
| East Asian | 0.0000544 | 0.0000544 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000178 | 0.0000176 |
| Middle Eastern | 0.0000544 | 0.0000544 |
| South Asian | 0.0000653 | 0.0000653 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development. Plays an important role in the development of several organs, including kidney, muscle and inner ear. Depending on context, functions as transcriptional repressor or activator. Lacks an activation domain, and requires interaction with EYA family members for transcription activation. Mediates nuclear translocation of EYA1 and EYA2. Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter. Regulates the expression of numerous genes, including MYC, CCND1 and EZR. Acts as activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2 (By similarity). Regulates the expression of CCNA1. {ECO:0000250, ECO:0000269|PubMed:15123840, ECO:0000269|PubMed:15141091, ECO:0000269|PubMed:19497856, ECO:0000269|PubMed:23435380}.;
- Disease
- DISEASE: Deafness, autosomal dominant, 23 (DFNA23) [MIM:605192]: A form of non-syndromic deafness characterized by prelingual, bilateral, symmetric hearing loss with a conductive component present in some but not all patients. {ECO:0000269|PubMed:15141091, ECO:0000269|PubMed:19497856, ECO:0000269|PubMed:23435380}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Branchiootic syndrome 3 (BOS3) [MIM:608389]: A syndrome characterized by usually bilateral branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, and structural defects of the outer, middle or inner ear. Otic defects include malformed and hypoplastic pinnae, a narrowed external ear canal, bulbous internal auditory canal, stapes fixation, malformed and hypoplastic cochlea. Branchial and otic anomalies overlap with those seen in individuals with the branchiootorenal syndrome. However renal anomalies are absent in branchiootic syndrome patients. {ECO:0000269|PubMed:15141091, ECO:0000269|PubMed:17637804, ECO:0000269|PubMed:18330911, ECO:0000269|PubMed:19497856, ECO:0000269|PubMed:21280147, ECO:0000269|PubMed:23435380}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable. {ECO:0000305|PubMed:15141091, ECO:0000305|PubMed:19497856}.;
- Pathway
- Transcriptional misregulation in cancer - Homo sapiens (human)
(Consensus)
Recessive Scores
- pRec
- 0.235
Intolerance Scores
- loftool
- rvis_EVS
- -0.3
- rvis_percentile_EVS
- 32.62
Haploinsufficiency Scores
- pHI
- 0.822
- hipred
- Y
- hipred_score
- 0.806
- ghis
- 0.658
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.860
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Six1
- Phenotype
- growth/size/body region phenotype; taste/olfaction phenotype; endocrine/exocrine gland phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; vision/eye phenotype; hematopoietic system phenotype; 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); 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); embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; limbs/digits/tail 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); hearing/vestibular/ear phenotype;
Zebrafish Information Network
- Gene name
- six1a
- Affected structure
- fast muscle cell
- Phenotype tag
- abnormal
- Phenotype quality
- decreased process quality
Gene ontology
- Biological process
- negative regulation of transcription by RNA polymerase II;ureteric bud development;branching involved in ureteric bud morphogenesis;organ induction;kidney development;outflow tract morphogenesis;regulation of transcription, DNA-templated;apoptotic process;pattern specification process;skeletal muscle tissue development;sensory perception of sound;cell population proliferation;regulation of synaptic growth at neuromuscular junction;regulation of skeletal muscle satellite cell proliferation;regulation of skeletal muscle cell proliferation;facial nerve morphogenesis;epithelial cell differentiation;thyroid gland development;olfactory placode formation;regulation of protein localization;protein localization to nucleus;aorta morphogenesis;inner ear morphogenesis;middle ear morphogenesis;negative regulation of neuron apoptotic process;regulation of neuron differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;thymus development;neuron fate specification;generation of neurons;embryonic cranial skeleton morphogenesis;embryonic skeletal system morphogenesis;skeletal muscle fiber development;inner ear development;anatomical structure development;regulation of epithelial cell proliferation;myoblast migration;pharyngeal system development;myotome development;fungiform papilla morphogenesis;trigeminal ganglion development;otic vesicle development;metanephric mesenchyme development;regulation of branch elongation involved in ureteric bud branching;positive regulation of ureteric bud formation;mesonephric tubule formation;ureter smooth muscle cell differentiation;positive regulation of secondary heart field cardioblast proliferation;cochlea morphogenesis;positive regulation of branching involved in ureteric bud morphogenesis;negative regulation of branching involved in ureteric bud morphogenesis;cellular response to 3,3',5-triiodo-L-thyronine;positive regulation of mesenchymal cell proliferation involved in ureter development;regulation of skeletal muscle cell differentiation
- Cellular component
- nucleus;transcription factor complex;nucleolus;cytoplasm
- Molecular function
- transcription regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;transcription coactivator binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;chromatin binding;DNA-binding transcription factor activity;protein binding;sequence-specific DNA binding;transcription regulatory region DNA binding