PAX3

paired box 3, the group of PRD class homeoboxes and pseudogenes|Paired boxes

Basic information

Region (hg38): 2:222199886-222298998

Previous symbols: [ "WS1" ]

Links

ENSG00000135903 ∙ NCBI:5077 ∙ OMIM:606597 ∙ HGNC:8617 ∙ Uniprot:P23760 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Waardenburg syndrome type 1 (Strong), mode of inheritance: AD
• Waardenburg syndrome type 1 (Strong), mode of inheritance: AR
• Waardenburg syndrome type 1 (Definitive), mode of inheritance: AD
• craniofacial-deafness-hand syndrome (Definitive), mode of inheritance: AD
• Waardenburg syndrome type 1 (Supportive), mode of inheritance: AD
• Waardenburg syndrome type 3 (Supportive), mode of inheritance: AD
• craniofacial-deafness-hand syndrome (Supportive), mode of inheritance: AD
• craniofacial-deafness-hand syndrome (Limited), mode of inheritance: Unknown
• Waardenburg syndrome type 3 (Strong), mode of inheritance: AR
• Waardenburg syndrome type 1 (Strong), mode of inheritance: AD
• Waardenburg syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Waardenburg syndrome, type 1; Waardenburg syndrome, type 3; Craniofacial-deafness-hand syndrome	AD/AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Musculoskeletal; Ophthalmologic	14902764; 6059431; 091186; 6859126; 1887852; 1347149; 1536170; 1347148; 1576755; 8423616; 8447316; 7981674; 8588597; 8533800; 7726174; 8664898; 9279758; 9654197; 11683776; 14556253; 12949970; 20024939; 20199465; 20478267; 20664692; 21965087
The condition may be clinically recognizable, especially in individuals with one allelic form, Waardenburg syndrome, type 3, which includes features such as upper limb anomalies; A homozygous individual has been described, with very severe phenotypic effects

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PAX3 gene.

• not provided (194 variants)
• Waardenburg syndrome type 1 (66 variants)
• Craniofacial-deafness-hand syndrome (44 variants)
• Waardenburg syndrome (42 variants)
• not specified (35 variants)
• Inborn genetic diseases (15 variants)
• PAX3-related condition (7 variants)
• Waardenburg syndrome type 3 (6 variants)
• Rare genetic deafness (3 variants)
• Hearing impairment (2 variants)
• Intellectual disability (2 variants)
• Congenital diaphragmatic hernia (1 variants)
• Waardenburg syndrome type 1;Waardenburg syndrome type 3;Craniofacial-deafness-hand syndrome (1 variants)
• Waardenburg syndrome type 1;Craniofacial-deafness-hand syndrome;Alveolar rhabdomyosarcoma;Waardenburg syndrome type 3 (1 variants)
• Waardenburg syndrome type 3;Alveolar rhabdomyosarcoma;Waardenburg syndrome type 1;Craniofacial-deafness-hand syndrome (1 variants)
• See cases (1 variants)
• Waardenburg syndrome type 1;Waardenburg syndrome type 3;Alveolar rhabdomyosarcoma;Craniofacial-deafness-hand syndrome (1 variants)
• Rare genetic deafness;Waardenburg syndrome (1 variants)
• Usher syndrome (1 variants)
• Waardenburg syndrome;Rare genetic deafness (1 variants)
• Ocular albinism with congenital sensorineural hearing loss (1 variants)
• Craniofacial-deafness-hand syndrome;Alveolar rhabdomyosarcoma;Waardenburg syndrome type 1;Waardenburg syndrome type 3 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PAX3 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		3	22	3	30
missense	11	28	67	8		114
nonsense	13	9	1	1		24
start loss						0
frameshift	21	10	1			32
inframe indel		1	1			2
splice donor/acceptor (+/-2bp)	2	4				6
splice region		1	5	1		7
non coding			9	26	25	60
Total	49	52	82	57	28

Highest pathogenic variant AF is 0.00000657

Variants in PAX3

This is a list of pathogenic ClinVar variants found in the PAX3 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-222201034-T-TAC			Benign (Aug 13, 2019)
2-222201151-C-A			Likely benign (Nov 11, 2021)
2-222201151-C-G			Benign (Jun 24, 2018)
2-222201169-G-T		PAX3-related disorder	Likely benign (Jul 01, 2019)
2-222201233-G-A		Waardenburg syndrome type 1	Pathogenic (-)
2-222201298-A-AC			Benign (Aug 21, 2019)
2-222201298-A-ACC			Likely benign (Aug 11, 2019)
2-222201405-C-G		Waardenburg syndrome type 1	Uncertain significance (Jan 29, 2019)
2-222201414-G-A		not specified	Likely benign (Jan 21, 2016)
2-222201459-G-A			Likely benign (Dec 21, 2020)
2-222201518-G-A			Benign (Jun 24, 2018)
2-222201724-G-A		Craniofacial-deafness-hand syndrome • Waardenburg syndrome	Benign (Jan 13, 2018)
2-222201743-G-A		Waardenburg syndrome • Craniofacial-deafness-hand syndrome	Uncertain significance (Jan 13, 2018)
2-222201758-C-T		Craniofacial-deafness-hand syndrome • Waardenburg syndrome	Benign (Jan 13, 2018)
2-222201779-C-A		Craniofacial-deafness-hand syndrome • Waardenburg syndrome	Uncertain significance (Jan 13, 2018)
2-222201817-CA-C			Likely benign (Aug 10, 2019)
2-222201817-C-CA		Waardenburg syndrome • Craniofacial-deafness-hand syndrome	Conflicting classifications of pathogenicity (Aug 10, 2019)
2-222201819-A-C		Craniofacial-deafness-hand syndrome • Waardenburg syndrome	Uncertain significance (Jan 12, 2018)
2-222201840-C-T		Waardenburg syndrome • Craniofacial-deafness-hand syndrome	Benign (Jan 12, 2018)
2-222201841-G-A		Craniofacial-deafness-hand syndrome • Waardenburg syndrome	Uncertain significance (Jan 12, 2018)
2-222201889-G-A		Waardenburg syndrome • Craniofacial-deafness-hand syndrome	Benign (Jan 13, 2018)
2-222201930-A-T			Likely benign (Jan 05, 2023)
2-222201965-G-T			Uncertain significance (Sep 27, 2022)
2-222201986-T-C			Uncertain significance (Sep 06, 2022)
2-222201988-CTGTAG-GGTGGAC		PAX3-related disorder	Likely pathogenic (Jul 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PAX3	protein_coding	protein_coding	ENST00000392069	10	99109

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.241	0.759	125694	0	54	125748	0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.62	206	283	0.729	0.0000158	3294
Missense in Polyphen		61	112.43	0.54258		1318
Synonymous	-0.683	123	114	1.08	0.00000707	993
Loss of Function	3.51	6	24.9	0.241	0.00000138	265

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.000108	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000355	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00160	0.00160
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor that may regulate cell proliferation, migration and apoptosis. Involved in neural development and myogenesis. Transcriptional activator of MITF, acting synergistically with SOX10 (PubMed:21965087). {ECO:0000269|PubMed:16951170, ECO:0000269|PubMed:21965087}.
• Disease: DISEASE: Waardenburg syndrome 1 (WS1) [MIM:193500]: WS1 is an autosomal dominant disorder characterized by non-progressive sensorineural deafness, pigmentary disturbances such as frontal white blaze of hair, heterochromia of irides, white eyelashes, leukoderma, and wide bridge of nose owing to lateral displacement of the inner canthus of each eye (dystopia canthorum). WS1 shows variable clinical expression and some affected individuals do not manifest hearing impairment or iris pigmentation disturbances. Dystopia canthorum is the most consistent sign and is found in 98% of the patients. {ECO:0000269|PubMed:10779847, ECO:0000269|PubMed:12949970, ECO:0000269|PubMed:1303193, ECO:0000269|PubMed:1347148, ECO:0000269|PubMed:1347149, ECO:0000269|PubMed:16971891, ECO:0000269|PubMed:20478267, ECO:0000269|PubMed:21965087, ECO:0000269|PubMed:7825605, ECO:0000269|PubMed:7833953, ECO:0000269|PubMed:7981674, ECO:0000269|PubMed:8447316, ECO:0000269|PubMed:8490648, ECO:0000269|PubMed:8533800, ECO:0000269|PubMed:8589691, ECO:0000269|PubMed:8845842, ECO:0000269|PubMed:9067759, ECO:0000269|PubMed:9452070, ECO:0000269|PubMed:9541113, ECO:0000269|Ref.35}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Waardenburg syndrome 3 (WS3) [MIM:148820]: WS3 is an autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, dystopia canthorum and limb anomalies such as hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, syndactylies. {ECO:0000269|PubMed:12949970, ECO:0000269|PubMed:7726174, ECO:0000269|PubMed:8447316, ECO:0000269|Ref.36}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Craniofacial-deafness-hand syndrome (CDHS) [MIM:122880]: Thought to be an autosomal dominant disease which comprises absence or hypoplasia of the nasal bones, hypoplastic maxilla, small and short nose with thin nares, limited movement of the wrist, short palpebral fissures, ulnar deviation of the fingers, hypertelorism and profound sensory-neural deafness. {ECO:0000269|PubMed:8664898}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Rhabdomyosarcoma 2 (RMS2) [MIM:268220]: A form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchymal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. {ECO:0000269|PubMed:8275086}. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving PAX3 is found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with FOXO1. The resulting protein is a transcriptional activator. {ECO:0000269|PubMed:8275086}.; DISEASE: Note=A chromosomal aberration involving PAX3 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with NCOA1 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. {ECO:0000269|PubMed:15313887}.
• Pathway: Transcriptional misregulation in cancer - Homo sapiens (human);Neural Crest Differentiation;Ectoderm Differentiation;Chromatin modifying enzymes;HATs acetylate histones;Chromatin organization;Regulation of retinoblastoma protein (Consensus)

Recessive Scores

• pRec: 0.680

Intolerance Scores

• loftool: 0.00923
• rvis_EVS: 0
• rvis_percentile_EVS: 53.85

Haploinsufficiency Scores

• pHI: 0.993
• hipred: Y
• hipred_score: 0.853
• ghis: 0.459

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.693

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pax3
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial 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); endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; immune system phenotype; skeleton phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear 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; normal 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); pigmentation phenotype; neoplasm; embryo phenotype

Zebrafish Information Network

• Gene name: pax3a
• Affected structure: melanoblast
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: transcription by RNA polymerase II;apoptotic process;nervous system development;muscle organ development;sensory perception of sound;animal organ morphogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II
• Cellular component: nucleoplasm
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;protein binding;sequence-specific DNA binding;HMG box domain binding