SIX3

SIX homeobox 3, the group of SINE class homeoboxes

Basic information

Region (hg38): 2:44941701-44946071

Previous symbols: [ "HPE2" ]

Links

ENSG00000138083 ∙ NCBI:6496 ∙ OMIM:603714 ∙ HGNC:10889 ∙ Uniprot:O95343 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• holoprosencephaly 5 (Definitive), mode of inheritance: AD
• holoprosencephaly 2 (Strong), mode of inheritance: AD
• holoprosencephaly (Supportive), mode of inheritance: AR
• holoprosencephaly 2 (Definitive), mode of inheritance: AD
• holoprosencephaly 2 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holoprosencephaly 2	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Endocrine; Neurologic; Ophthalmologic	10369266; 15221788; 16199538; 17001667; 19346217; 19353631; 20157829; 20531442; 21940735; 21976454; 23112757
Variants in SIX3 have also been implicated in schizencephaly, but the data are unclear, and this may have co-occurred with typical holoprosencephaly-type malformations; Individuals with holoprosencephaly may demonstrate endocrine anomalies

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SIX3 gene.

• Holoprosencephaly 2 (99 variants)
• not provided (70 variants)
• not specified (11 variants)
• Inborn genetic diseases (10 variants)
• SIX3-related condition (4 variants)
• Schizencephaly (3 variants)
• Schizencephaly;Holoprosencephaly 2 (2 variants)
• Holoprosencephaly 2;Schizencephaly (1 variants)
• Solitary median maxillary central incisor syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SIX3 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			6	43	3	52
missense	3	4	53	3	2	65
nonsense	3					3
start loss		1				1
frameshift	6	3				9
inframe indel	1		7			8
splice donor/acceptor (+/-2bp)	1	1				2
splice region				2		2
non coding			1	2	5	8
Total	14	9	67	48	10

Variants in SIX3

This is a list of pathogenic ClinVar variants found in the SIX3 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-44941782-C-T			Likely benign (Sep 16, 2018)
2-44941807-TCTCTCC-T			Benign (Jan 17, 2020)
2-44942103-C-G			Uncertain significance (Oct 02, 2014)
2-44942105-A-G			Likely pathogenic (Mar 06, 2018)
2-44942110-A-C		Holoprosencephaly 2	Likely benign (Oct 03, 2022)
2-44942123-C-A		Holoprosencephaly 2	Uncertain significance (Nov 27, 2023)
2-44942123-CT-C		Holoprosencephaly 2	Pathogenic (Jul 17, 2023)
2-44942128-CCT-C			Likely pathogenic (Jun 25, 2023)
2-44942143-C-T		Holoprosencephaly 2	Likely benign (Nov 28, 2021)
2-44942145-T-G		Holoprosencephaly 2	Uncertain significance (Sep 26, 2023)
2-44942146-C-T			Likely benign (Jun 19, 2018)
2-44942147-T-C			Likely benign (Jun 08, 2018)
2-44942152-G-A		Holoprosencephaly 2	Likely benign (Aug 02, 2023)
2-44942156-A-T		Holoprosencephaly 2	Uncertain significance (Oct 23, 2021)
2-44942161-C-T		Holoprosencephaly 2	Likely benign (Feb 04, 2022)
2-44942162-G-T		Holoprosencephaly 2	Benign (Oct 13, 2023)
2-44942164-C-A		Holoprosencephaly 2	Likely benign (Apr 25, 2023)
2-44942165-G-A		Holoprosencephaly 2	Uncertain significance (May 04, 2022)
2-44942165-G-T		Inborn genetic diseases	Uncertain significance (Jun 16, 2023)
2-44942183-A-G		Holoprosencephaly 2	Uncertain significance (Aug 30, 2023)
2-44942190-T-C		Holoprosencephaly 2 • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 22, 2022)
2-44942194-G-T		Holoprosencephaly 2 • not specified	Benign (Jan 30, 2024)
2-44942196-G-C		Holoprosencephaly 2	Uncertain significance (Nov 08, 2022)
2-44942197-TAGCGGCGGCGGGAACGGTGCGGGAGGCGGCGGCGGCGCGGGAGGCGGC-T		Holoprosencephaly 2	Uncertain significance (Jan 13, 2024)
2-44942200-C-T		Holoprosencephaly 2 • SIX3-related disorder	Likely benign (Oct 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SIX3	protein_coding	protein_coding	ENST00000260653	2	4315

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.947	0.0527	117557	0	2	117559	0.00000851

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.07	119	202	0.589	0.00000935	2093
Missense in Polyphen		22	66.481	0.33092		684
Synonymous	-1.87	112	89.5	1.25	0.00000429	691
Loss of Function	2.82	0	9.27	0.00	4.01e-7	98

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000585	0.0000585
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 AND CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is AES and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 functions also in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway (By similarity). Plays a role in eye development by suppressing WNT1 expression and in dorsal- ventral patterning by repressing BMP signaling pathway. {ECO:0000250|UniProtKB:Q62233, ECO:0000269|PubMed:18791198}.
• Disease: DISEASE: Holoprosencephaly 2 (HPE2) [MIM:157170]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. {ECO:0000269|PubMed:10369266, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15523651, ECO:0000269|PubMed:17001667, ECO:0000269|PubMed:18791198, ECO:0000269|PubMed:20531442}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Schizencephaly (SCHZC) [MIM:269160]: Extremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. Large portions of the cerebral hemispheres may be absent and replaced by cerebro- spinal fluid. {ECO:0000269|PubMed:20157829}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Preimplantation Embryo (Consensus)

Recessive Scores

• pRec: 0.218

Intolerance Scores

• loftool: 0.0812
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.26

Haploinsufficiency Scores

• pHI: 0.873
• hipred: Y
• hipred_score: 0.713
• ghis: 0.474

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.958

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Six3
• Phenotype: craniofacial phenotype; growth/size/body region phenotype; taste/olfaction 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); digestive/alimentary phenotype; vision/eye phenotype; skeleton phenotype; embryo phenotype; respiratory system phenotype; 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)

Gene ontology

• Biological process: obsolete protein import into nucleus, translocation;eye development;epithelial cell maturation;lens development in camera-type eye;optic vesicle morphogenesis;brain development;visual perception;proximal/distal axis specification;neuroblast differentiation;telencephalon development;forebrain anterior/posterior pattern specification;forebrain dorsal/ventral pattern formation;cell proliferation in forebrain;telencephalon regionalization;pituitary gland development;negative regulation of Wnt signaling pathway;regulation of cell population proliferation;negative regulation of neuron differentiation;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;circadian behavior;anatomical structure development;lens induction in camera-type eye;regulation of neural retina development;lens fiber cell differentiation;neuroblast migration;regulation of cell cycle phase transition;regulation of neuroblast proliferation;apoptotic process involved in development;lens fiber cell apoptotic process;regulation of neural precursor cell proliferation
• Cellular component: nucleus;transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;transcription corepressor binding;DNA-binding transcription factor activity;transcription coactivator activity;signaling receptor binding;protein binding;histone deacetylase binding