PITX1

paired like homeodomain 1, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 5:135027734-135034813

Previous symbols: [ "BFT" ]

Links

ENSG00000069011 ∙ NCBI:5307 ∙ OMIM:602149 ∙ HGNC:9004 ∙ Uniprot:P78337 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• clubfoot (Strong), mode of inheritance: AD
• brachydactyly-elbow wrist dysplasia syndrome (Supportive), mode of inheritance: AD
• brachydactyly-elbow wrist dysplasia syndrome (Limited), mode of inheritance: AD
• clubfoot (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly; Liebenberg syndrome	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; Musculoskeletal	18950742; 21775501; 22258522; 23022097
Liebenberg syndrome may be caused by abornmal gene expression due to gene-regulatory anomalies

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PITX1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PITX1 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				9	3	12
missense		2	40		2	44
nonsense						0
start loss						0
frameshift		3	1			4
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region						0
non coding				2	10	12
Total	0	6	42	11	15

Variants in PITX1

This is a list of pathogenic ClinVar variants found in the PITX1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-135028716-TCCGCGC-T			Benign (May 14, 2021)
5-135028725-G-A			Benign (May 15, 2021)
5-135028784-T-C		not specified	Uncertain significance (Nov 06, 2023)
5-135028790-A-G		Brachydactyly-elbow wrist dysplasia syndrome	Uncertain significance (Oct 19, 2020)
5-135028797-C-A			Likely benign (Oct 25, 2022)
5-135028798-G-C		not specified	Uncertain significance (May 18, 2023)
5-135028801-T-C			Uncertain significance (Aug 26, 2022)
5-135028809-C-T			Likely benign (Nov 13, 2023)
5-135028810-G-A		not specified	Uncertain significance (Aug 28, 2023)
5-135028825-A-C			Uncertain significance (Mar 20, 2023)
5-135028828-C-G		not specified • Clubfoot • Brachydactyly-elbow wrist dysplasia syndrome	Benign (Jan 31, 2024)
5-135028867-C-A			Uncertain significance (Dec 04, 2023)
5-135028900-C-T		Clubfoot	Uncertain significance (Apr 04, 2024)
5-135028917-C-G			Likely benign (Jun 21, 2022)
5-135028924-GGAGTGCCGTACGGGCAAGCGCCCGGCGACATGGCC-G		Clubfoot	Pathogenic (Jun 01, 2012)
5-135028930-C-A		not specified	Uncertain significance (Dec 12, 2023)
5-135028931-C-A		Micrognathia • not specified	Conflicting classifications of pathogenicity (May 04, 2022)
5-135028931-C-T		Brachydactyly-elbow wrist dysplasia syndrome;Clubfoot	Benign (Sep 22, 2021)
5-135028936-G-A		not specified	Uncertain significance (Feb 06, 2023)
5-135028968-C-CG			Uncertain significance (Sep 19, 2022)
5-135028985-TG-T			Likely pathogenic (Jan 01, 2023)
5-135029013-C-T			Uncertain significance (Nov 03, 2023)
5-135029030-C-T		not specified	Uncertain significance (Jul 26, 2022)
5-135029033-G-A			Uncertain significance (Mar 01, 2022)
5-135029038-A-G		PITX1-related disorder	Uncertain significance (Mar 31, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PITX1	protein_coding	protein_coding	ENST00000265340	3	7079

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.882	0.117	121418	0	1	121419	0.00000412

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.31	138	189	0.732	0.00000933	2030
Missense in Polyphen		33	61.63	0.53546		735
Synonymous	-1.12	95	82.1	1.16	0.00000437	638
Loss of Function	2.85	1	11.4	0.0881	4.92e-7	115

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000910	0.00000910
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Sequence-specific transcription factor that binds gene promoters and activates their transcription. May play a role in the development of anterior structures, and in particular, the brain and facies and in specifying the identity or structure of hindlimb. {ECO:0000250|UniProtKB:P56673}.
• Disease: DISEASE: Clubfoot, congenital, with or without deficiency of long bones and/or mirror-image polydactyly (CCF) [MIM:119800]: A congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities. Clubfoot may occur in isolation or as part of a syndrome. Some patients present tibial hemimelia, bilateral patellar hypoplasia, and preaxial mirror-image polydactyly. {ECO:0000269|PubMed:18950742, ECO:0000269|PubMed:22258522}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Liebenberg syndrome (LBNBG) [MIM:186550]: An upper limb- malformation syndrome characterized by the combination of dysplastic elbow joints and the fusion of wrist bones with consequent radial deviation. {ECO:0000269|PubMed:23022097}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving the PITX1 locus results in LBNBG. Translocation t(5;18)(q31.1;q12.3). Additionally, two chromosome 5 deletions located 5'of PITX1 have been found in LBNBG patients. These structural variations cause altered expression of PITX1 in the forelimb via the activation of ectopic enhancers (PubMed:23022097). {ECO:0000269|PubMed:23022097}.

Recessive Scores

• pRec: 0.273

Intolerance Scores

• loftool: 0.105
• rvis_EVS: -0.14
• rvis_percentile_EVS: 43.29

Haploinsufficiency Scores

• pHI: 0.628
• hipred: Y
• hipred_score: 0.697
• ghis: 0.524

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.994

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pitx1
• Phenotype: muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); skeleton phenotype; digestive/alimentary 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; limbs/digits/tail 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

Gene ontology

• Biological process: skeletal system development;anatomical structure morphogenesis;branchiomeric skeletal muscle development;pituitary gland development;embryonic hindlimb morphogenesis;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;myoblast fate commitment;cartilage development
• Cellular component: nucleus;transcription factor complex;nucleolus;cytoplasm
• 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;DNA-binding transcription factor activity;protein binding;sequence-specific DNA binding