SIX1

SIX homeobox 1, the group of SINE class homeoboxes

Basic information

Region (hg38): 14:60643420-60658259

Previous symbols: [ "DFNA23" ]

Links

ENSG00000126778 ∙ NCBI:6495 ∙ OMIM:601205 ∙ HGNC:10887 ∙ Uniprot:Q15475 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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

Clinical Genomic Database

Source: CGD

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 ClinVar and linked to the SIX1 gene.

• not provided (70 variants)
• Branchiootic syndrome 3 (62 variants)
• Autosomal dominant nonsyndromic hearing loss 23 (50 variants)
• Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23 (35 variants)
• Autosomal dominant nonsyndromic hearing loss 23;Branchiootic syndrome 3 (11 variants)
• Nonsyndromic Hearing Loss, Dominant (10 variants)
• Branchiootorenal Spectrum Disorders (10 variants)
• not specified (6 variants)
• Inborn genetic diseases (6 variants)
• Hearing impairment (3 variants)
• Branchiootic syndrome 3;Branchiootorenal syndrome 1;Autosomal dominant nonsyndromic hearing loss 23 (3 variants)
• Branchiootorenal syndrome 1;Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23 (2 variants)
• SIX1-related condition (1 variants)
• Branchiootic syndrome 1 (1 variants)
• Autosomal dominant nonsyndromic hearing loss 23;Branchiootic syndrome 3;Branchiootorenal syndrome 1 (1 variants)
• Unilateral deafness (1 variants)
• Autosomal dominant nonsyndromic hearing loss (1 variants)
• Melnick-Fraser syndrome (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.

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			3	29		32
missense	2	8	43	2		55
nonsense			2			2
start loss			2			2
frameshift	1		5			6
inframe indel		1	1			2
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding			23	23	10	56
Total	3	9	79	54	10

Variants in SIX1

This is a list of pathogenic ClinVar variants found in the SIX1 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-60644712-A-G		Branchiootorenal Spectrum Disorders • Nonsyndromic Hearing Loss, Dominant	Uncertain significance (Jun 14, 2016)
14-60644787-G-A		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Benign (Jan 13, 2018)
14-60645011-CAT-C		Nonsyndromic Hearing Loss, Dominant • Branchiootorenal Spectrum Disorders	Uncertain significance (Jun 14, 2016)
14-60645032-T-C		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Uncertain significance (Jan 13, 2018)
14-60645051-A-G		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Uncertain significance (Jan 13, 2018)
14-60645203-T-A		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Uncertain significance (Jan 13, 2018)
14-60645204-A-T		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Benign/Likely benign (Jan 13, 2018)
14-60645239-C-A		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Benign/Likely benign (Jan 13, 2018)
14-60645274-GT-G		Nonsyndromic Hearing Loss, Dominant • Branchiootorenal Spectrum Disorders	Likely benign (Jun 14, 2016)
14-60645282-A-G		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Uncertain significance (Jan 12, 2018)
14-60645386-CAAACTAG-C		Branchiootorenal Spectrum Disorders • Nonsyndromic Hearing Loss, Dominant	Likely benign (Jun 14, 2016)
14-60645425-G-A		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Uncertain significance (Jan 13, 2018)
14-60645516-T-A		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Likely benign (Apr 27, 2017)
14-60645516-TA-T		Nonsyndromic Hearing Loss, Dominant • Branchiootorenal Spectrum Disorders	Benign (Jun 14, 2016)
14-60645516-TAA-T		Branchiootorenal Spectrum Disorders • Nonsyndromic Hearing Loss, Dominant	Uncertain significance (Jun 14, 2016)
14-60645517-A-T		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Uncertain significance (Jan 13, 2018)
14-60645528-A-C		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Uncertain significance (Jan 13, 2018)
14-60645547-A-C		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Uncertain significance (Jan 12, 2018)
14-60645595-G-A		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Uncertain significance (Jan 13, 2018)
14-60645681-C-G		Branchiootic syndrome 3 • Autosomal dominant nonsyndromic hearing loss 23	Benign (Jan 12, 2018)
14-60645701-CTAAA-C		Nonsyndromic Hearing Loss, Dominant • Branchiootorenal Spectrum Disorders	Likely benign (Jun 14, 2016)
14-60645840-T-C		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Benign/Likely benign (Jan 13, 2018)
14-60645879-T-C		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Benign (Jan 13, 2018)
14-60645912-T-C		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Uncertain significance (Jan 13, 2018)
14-60645949-G-C		Autosomal dominant nonsyndromic hearing loss 23 • Branchiootic syndrome 3	Benign (Jan 12, 2018)

GnomAD

Source: gnomAD

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: dbNSFP

• 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

• 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