PITX3

paired like homeodomain 3, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 10:102230189-102241512

Previous symbols: [ "ASMD" ]

Links

ENSG00000107859 ∙ NCBI:5309 ∙ OMIM:602669 ∙ HGNC:9006 ∙ Uniprot:O75364 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cataract 11 multiple types (Definitive), mode of inheritance: AD
• anterior segment dysgenesis 1 (Definitive), mode of inheritance: AD
• cataract 9 multiple types (Definitive), mode of inheritance: AD
• anterior segment dysgenesis 1 (Strong), mode of inheritance: AD
• anterior segment dysgenesis 1 (Moderate), mode of inheritance: AD
• cataract-glaucoma syndrome (Supportive), mode of inheritance: AD
• early-onset posterior polar cataract (Supportive), mode of inheritance: AD
• cataract 11 multiple types (Strong), mode of inheritance: AD
• anterior segment dysgenesis 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cataract 11, multiple types; Cataract 11, syndromic; Anterior segment dysgenesis 1	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	Ophthalmologic	6801987; 9620774; 10361984; 15286169; 16565358; 17888164; 18989383; 21633712; 22223473

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PITX3 gene.

• not provided (2 variants)
• Cataract 11 multiple types (1 variants)
• Cataract 11, posterior polar (1 variants)
• ANTERIOR SEGMENT DYSGENESIS 1, MULTIPLE SUBTYPES (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PITX3 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	8	1	11
missense			23			23
nonsense		2	1			3
start loss						0
frameshift	2	1	1			4
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				2	2	4
Total	2	3	28	10	3

Variants in PITX3

This is a list of pathogenic ClinVar variants found in the PITX3 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-102230515-C-A		Developmental cataract	Likely pathogenic (May 01, 2021)
10-102230579-C-A		Inborn genetic diseases	Uncertain significance (Jun 18, 2024)
10-102230650-T-C			Uncertain significance (Feb 01, 2021)
10-102230652-C-T			Likely benign (Feb 03, 2022)
10-102230661-G-T		PITX3-related disorder	Likely pathogenic (Jun 11, 2018)
10-102230664-G-A		PITX3-related disorder	Likely benign (Mar 01, 2019)
10-102230683-G-A		Inborn genetic diseases	Uncertain significance (Jun 29, 2023)
10-102230682-C-CGCG			Uncertain significance (Aug 31, 2022)
10-102230685-G-A		PITX3-related disorder	Likely benign (Mar 05, 2024)
10-102230720-C-T		PITX3-related disorder	Uncertain significance (Aug 24, 2023)
10-102230724-C-T			Likely benign (Sep 15, 2022)
10-102230741-C-T			Uncertain significance (Jul 27, 2022)
10-102230746-G-A		Inborn genetic diseases	Uncertain significance (Nov 03, 2022)
10-102230746-G-T		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
10-102230753-CG-C			Uncertain significance (Aug 09, 2023)
10-102230754-G-A			Likely benign (Dec 30, 2023)
10-102230761-C-G			Uncertain significance (Dec 01, 2023)
10-102230762-C-T			Uncertain significance (Jul 29, 2023)
10-102230765-C-CGGCCCTGCAGGGTCTGG			Pathogenic (Jul 12, 2021)
10-102230766-GCCCAGGCCCTGCAGGGC-G		Cataract 11 multiple types	Likely pathogenic (Jan 19, 2024)
10-102230766-G-GCCCAGGCCCTGCAGGGC		Cataract 11, posterior polar • ANTERIOR SEGMENT DYSGENESIS 1, MULTIPLE SUBTYPES • Cataract 11 multiple types • PITX3-related disorder	Pathogenic (Jun 15, 2023)
10-102230772-GC-G		Cataract 11, posterior polar, with microphthalmia and neurodevelopmental abnormalities • Cataract 11, posterior polar	Pathogenic (Apr 01, 2006)
10-102230777-G-A			Likely pathogenic (Feb 10, 2016)
10-102230785-C-CCA			Pathogenic (Jun 14, 2021)
10-102230793-T-G		PITX3-related disorder	Likely benign (Jun 17, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PITX3	protein_coding	protein_coding	ENST00000370002	3	11289

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.813	0.186	110771	0	1	110772	0.00000451

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.50	115	170	0.677	0.00000791	1874
Missense in Polyphen		14	38.755	0.36124		408
Synonymous	0.542	75	81.2	0.923	0.00000395	666
Loss of Function	2.62	1	9.90	0.101	4.24e-7	108

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000315	0.0000315
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 is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. In addition to its importance during development, it also has roles in the long-term survival and maintenance of the mdDA neurons. Activates NR4A2/NURR1- mediated transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons. Acts by decreasing the interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state. Essential for the normal lens development and differentiation. Plays a critical role in the maintenance of mitotic activity of lens epithelial cells, fiber cell differentiation and in the control of the temporal and spatial activation of fiber cell-specific crystallins. Positively regulates FOXE3 expression and negatively regulates PROX1 in the anterior lens epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2 and thus maintains lens epithelial cells in cell cycle (By similarity). {ECO:0000250}.
• Disease: DISEASE: Cataract 11, multiple types (CTRCT11) [MIM:610623]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT11 includes posterior polar cataract, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Some CTRCT11 patients can present a severe phenotype including microphthalmia and neurological dysfunction. {ECO:0000269|PubMed:15286169, ECO:0000269|PubMed:9620774}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Dopaminergic Neurogenesis (Consensus)

Recessive Scores

• pRec: 0.193

Haploinsufficiency Scores

• pHI: 0.445
• hipred: Y
• hipred_score: 0.736
• ghis: 0.665

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.647

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pitx3
• Phenotype: immune system phenotype; skeleton 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); vision/eye 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); hematopoietic system phenotype; reproductive system phenotype; pigmentation phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: pitx3
• Affected structure: mandibular arch skeleton
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: lens development in camera-type eye;lens morphogenesis in camera-type eye;regulation of transcription, DNA-templated;aging;locomotory behavior;anatomical structure morphogenesis;animal organ morphogenesis;negative regulation of gliogenesis;midbrain development;response to immobilization stress;response to cocaine;response to morphine;positive regulation of neuron apoptotic process;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;neuron development;lens fiber cell differentiation;dopaminergic neuron differentiation;response to methamphetamine hydrochloride;positive regulation of cell proliferation in midbrain;cellular response to glial cell derived neurotrophic factor
• Cellular component: nucleus;neuronal cell body
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II transcription factor binding;sequence-specific DNA binding