SIX5

protein-coding

SIX homeobox 5, the group of SINE class homeoboxes

Gene summary

The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

Previous symbols:

DMAHP

MANE transcript

NM_175875.5

Inheritance

ClinVar variants

P:3U:342B:222

Top phenotype

Branchiootorenal syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr19:45,764,785-45,769,252

External References & Databases

Ensembl (ENSG00000177045)

Transcript & Mutation Effects

hg38 • Region Span ~4.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

branchio-oto-renal syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007029

Submitter: Orphanet

branchiootorenal syndrome 2NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0012575

Submitter: PanelApp Australia

branchio-oto-renal syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0007029

Submitter: ClinGen

The SIX5 gene has been associated with autosomal dominant branchio-oto-renal syndrome using the ClinGen Clinical Validity Framework as of 4/20/2017. This association was made using case-level data only. At least 5 missense variants have been reported in humans. SIX5 was first associated with this disease in humans as early as 2007 (Hoskins et al.). Association has been reported in at least 6 probands in 2 publications (17357085, 24429398), however the reported variants are high in frequency in population databases, have no evidence of pathogenicity, and/or an alternate cause of disease has later been reported (21280147). This gene-disease association is supported by protein interaction and biochemical function studies (14704431, 17357085, 11950062). While EYA1 and SIX1 gene inactivation in mice leads to ear and kidney abnormalities, two independent SIX5 mouse models have cataracts and no ear or kidney abnormalities (10802667, 10802668). In summary, there is convincing evidence disputing the association between SIX5 and autosomal dominant branchio-oto-renal syndrome. More evidence is needed to either support or refute the role SIX5 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/2018.

branchiootorenal syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012575

Submitter: G2P

branchiootorenal syndrome 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012575

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Branchiootorenal syndrome 2AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Renal

Intervention: Audiologic/Otolaryngologic; Renal

Rationale: 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

Comments: Individuals can have characteristic aural anomalies, but these may not be readily ascertained

Refs: 17357085; 20301554

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIX5 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 396

not specifiedTotal: 205

Branchiootorenal syndrome 2Total: 155

SIX5-related disorderTotal: 97

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_175875.5. 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	164 clinvar	1 clinvar	174
missense	1 clinvar		318 clinvar	56 clinvar	1 clinvar	376
nonsense		2 clinvar	4 clinvar			6
start loss						0
frameshift			10 clinvar			10
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	2	342	220	2	567

Highest pathogenic variant AF is 0.0000038846215

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_175875.5	RefSeq	NP_787071.3	3	MANE Select
ENST00000317578.7	Ensembl	ENSP00000316842.4	3	MANE Select
ENST00000560160.1	Ensembl	ENSP00000453239.2	2	Standard
ENST00000560168.1	Ensembl	ENSP00000453189.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

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

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

Cellular Component

nucleus
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000317578
Coding exons: 3
Length: 4442
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 19
Defined: 125691
p: 0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.563	402	371	1.08	0.0000200	4472
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000065	0.000065	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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