SIX5

SIX homeobox 5, the group of SINE class homeoboxes

Basic information

Region (hg38): 19:45764785-45769252

Previous symbols: [ "DMAHP" ]

Links

ENSG00000177045 ∙ NCBI:147912 ∙ OMIM:600963 ∙ HGNC:10891 ∙ Uniprot:Q8N196 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• branchiootorenal syndrome 2 (Limited), mode of inheritance: AD
• branchiootorenal syndrome 2 (Definitive), mode of inheritance: AD
• branchio-oto-renal syndrome (Supportive), mode of inheritance: AD
• branchiootorenal syndrome 2 (Limited), mode of inheritance: Unknown
• branchio-oto-renal syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Branchiootorenal syndrome 2	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	17357085; 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 SIX5 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIX5 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	103	3	108
missense			164	12	4	180
nonsense			4			4
start loss						0
frameshift			1			1
inframe indel			9	2		11
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding				15	12	27
Total	0	0	180	132	19

Variants in SIX5

This is a list of pathogenic ClinVar variants found in the SIX5 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-45765170-G-A			Benign (Dec 23, 2018)
19-45765195-C-T			Benign (Dec 23, 2018)
19-45765340-G-C			Likely benign (Dec 12, 2018)
19-45765396-G-A			Likely benign (Jun 13, 2018)
19-45765456-C-T			Benign (Jul 05, 2018)
19-45765469-A-G			Likely benign (Sep 23, 2018)
19-45765506-G-A			Likely benign (Oct 22, 2023)
19-45765518-C-G			Uncertain significance (Dec 06, 2023)
19-45765528-C-A			Likely benign (Aug 27, 2023)
19-45765529-A-G			Uncertain significance (Mar 04, 2023)
19-45765532-G-A			Conflicting classifications of pathogenicity (Oct 23, 2021)
19-45765544-G-C		not specified	Uncertain significance (Nov 10, 2022)
19-45765548-G-A		not specified • Branchiootorenal syndrome 2	Benign/Likely benign (Jan 30, 2024)
19-45765551-C-T			Uncertain significance (Jan 16, 2022)
19-45765560-C-T		not specified	Conflicting classifications of pathogenicity (May 28, 2024)
19-45765571-C-T		not specified	Uncertain significance (May 30, 2024)
19-45765576-G-A		SIX5-related disorder	Likely benign (Dec 17, 2023)
19-45765581-C-T			Uncertain significance (Jul 09, 2022)
19-45765623-C-T		not specified	Uncertain significance (Nov 13, 2023)
19-45765624-G-A			Likely benign (Jan 08, 2024)
19-45765626-G-A		not specified	Uncertain significance (Mar 31, 2023)
19-45765633-C-T			Likely benign (May 17, 2023)
19-45765644-C-T		not specified • Branchiootorenal syndrome 2	Benign (Jan 31, 2024)
19-45765645-G-C			Likely benign (Jun 21, 2023)
19-45765655-G-T		not specified	Uncertain significance (Mar 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SIX5	protein_coding	protein_coding	ENST00000317578	3	4442

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00692	0.977	125672	0	19	125691	0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.563	402	371	1.08	0.0000200	4472
Missense in Polyphen		112	119.49	0.93731		1471
Synonymous	-4.64	268	187	1.43	0.0000119	1765
Loss of Function	2.11	6	14.8	0.406	6.87e-7	177

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000549	0.0000544
Finnish	0.0000471	0.0000462
European (Non-Finnish)	0.000112	0.000106
Middle Eastern	0.0000549	0.0000544
South Asian	0.0000654	0.0000653
Other	0.000343	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor that is thought to be involved in regulation of organogenesis. May be involved in determination and maintenance of retina formation. Binds a 5'-GGTGTCAG-3' motif present in the ARE regulatory element of ATP1A1. Binds a 5'- TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the myogenin promoter, and in the IGFBP5 promoter (By similarity). Thought to be regulated by association with Dach and Eya proteins, and seems to be coactivated by EYA1, EYA2 and EYA3 (By similarity). {ECO:0000250}.
• Disease: DISEASE: Branchiootorenal syndrome 2 (BOR2) [MIM:610896]: A syndrome characterized by branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, structural defects of the outer, middle or inner ear, and renal malformations. {ECO:0000269|PubMed:17357085}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.191

Haploinsufficiency Scores

• pHI: 0.172
• hipred: Y
• hipred_score: 0.519
• ghis: 0.595

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Six5
• Phenotype: endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; vision/eye phenotype; reproductive system phenotype

Gene ontology

• Biological process: lens development in camera-type eye;spermatid development;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;anatomical structure development;negative regulation of skeletal muscle satellite cell proliferation
• Cellular component: nucleus;transcription factor complex;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;protein binding