MSX1

msh homeobox 1, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 4:4859664-4863936

Previous symbols: [ "HOX7" ]

Links

ENSG00000163132 ∙ NCBI:4487 ∙ OMIM:142983 ∙ HGNC:7391 ∙ Uniprot:P28360 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• orofacial cleft 5 (Definitive), mode of inheritance: AD
• tooth and nail syndrome (Supportive), mode of inheritance: AD
• tooth agenesis (Supportive), mode of inheritance: AD
• tooth agenesis, selective, 1 (Strong), mode of inheritance: AD
• tooth and nail syndrome (Limited), mode of inheritance: AD
• tooth agenesis, selective, 1 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Orofacial cleft 5; Tooth agenesis, selective, 1, with/without orofacial cleft; Witkop 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; Dental; Dermatologic	8696335; 10742093; 11369996; 12097313; 12807959; 15264286; 15354328; 16327884; 16498076; 16868654; 16932841; 18374898; 19346736; 21297014; 21626677; 22297032

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MSX1 gene.

• Hypoplastic enamel-onycholysis-hypohidrosis syndrome (56 variants)
• not provided (23 variants)
• Inborn genetic diseases (15 variants)
• MSX1-related condition (3 variants)
• Orofacial cleft 5 (2 variants)
• MSX1-related selective tooth agenesis with or without orofacial cleft (1 variants)
• Orofacial cleft 5;Tooth agenesis, selective, 1 (1 variants)
• MSX1-related disorder (1 variants)
• Craniosynostosis syndrome (1 variants)
• Hypoplastic enamel-onycholysis-hypohidrosis syndrome;Tooth agenesis, selective, 1;Orofacial cleft 5 (1 variants)
• Tooth agenesis, selective, 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MSX1 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				10	3	13
missense			41	10	4	55
nonsense	3	1	1			5
start loss						0
frameshift	3		2			5
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			1		11	12
Total	6	1	45	20	18

Variants in MSX1

This is a list of pathogenic ClinVar variants found in the MSX1 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-4859882-G-A			Benign (Nov 12, 2018)
4-4859893-G-T		MSX1-related disorder	Likely benign (Jul 12, 2019)
4-4859957-G-A		Inborn genetic diseases	Uncertain significance (Jun 16, 2023)
4-4859964-G-A		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Aug 23, 2023)
4-4859976-G-C		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Jun 08, 2021)
4-4859979-G-GA		Tooth agenesis, selective, 1	Pathogenic (Mar 01, 2006)
4-4859985-C-T		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Benign (Jan 18, 2024)
4-4859988-G-A		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Apr 02, 2020)
4-4859988-G-C		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Uncertain significance (Jul 06, 2017)
4-4859993-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
4-4859993-G-T			Uncertain significance (Jun 13, 2022)
4-4859994-C-T		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Jan 13, 2024)
4-4859999-A-G		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Uncertain significance (Feb 15, 2022)
4-4860001-C-G		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Uncertain significance (Feb 18, 2020)
4-4860002-G-A		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
4-4860005-G-A		Inborn genetic diseases	Likely benign (Apr 07, 2023)
4-4860007-C-A		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Jun 04, 2022)
4-4860018-C-G		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Benign (Jan 29, 2024)
4-4860022-C-A		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Jul 21, 2016)
4-4860026-A-C		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Benign (Nov 06, 2023)
4-4860029-G-A		Inborn genetic diseases	Uncertain significance (Oct 27, 2022)
4-4860050-A-G		Hypoplastic enamel-onycholysis-hypohidrosis syndrome • MSX1-related disorder	Benign (Jun 29, 2023)
4-4860094-G-A		Hypoplastic enamel-onycholysis-hypohidrosis syndrome	Likely benign (Sep 10, 2020)
4-4860095-C-A		Inborn genetic diseases	Uncertain significance (Dec 06, 2022)
4-4860099-T-A		Tooth agenesis, selective, 1	Pathogenic (Apr 01, 2002)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MSX1	protein_coding	protein_coding	ENST00000382723	2	4271

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.165	0.778	124097	0	3	124100	0.0000121

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.278	158	168	0.940	0.0000100	1870
Missense in Polyphen		40	66.307	0.60325		690
Synonymous	-1.45	97	80.5	1.21	0.00000492	669
Loss of Function	1.57	2	6.22	0.321	2.65e-7	80

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000644	0.0000640
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000196	0.0000179
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a transcriptional repressor. May play a role in limb-pattern formation. Acts in cranofacial development and specifically in odontogenesis. Expression in the developing nail bed mesenchyme is important for nail plate thickness and integrity. {ECO:0000269|PubMed:11369996, ECO:0000269|PubMed:12807959}.
• Disease: DISEASE: Tooth agenesis, selective, 1 (STHAG1) [MIM:106600]: A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). STHAG1 can be associated with orofacial cleft in some patients. {ECO:0000269|PubMed:12097313, ECO:0000269|PubMed:8696335}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=MSX1 is deleted in some patients with Wolf- Hirschhorn syndrome (WHS). WHS results from sub-telomeric deletions in the short arm of chromosome 4. {ECO:0000305|PubMed:1969845}.; DISEASE: Ectodermal dysplasia 3, Witkop type (ECTD3) [MIM:189500]: A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD3 is characterized by abnormalities largely limited largely to teeth (some of which are missing) and nails (which are poorly formed early in life, especially toenails). This condition is distinguished from anhidrotic ectodermal dysplasia by autosomal dominant inheritance and little involvement of hair and sweat glands. The teeth are not as severely affected. {ECO:0000269|PubMed:11369996}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Non-syndromic orofacial cleft 5 (OFC5) [MIM:608874]: A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. {ECO:0000269|PubMed:12807959}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: HTLV-I infection - Homo sapiens (human);Neural Crest Differentiation;Dopaminergic Neurogenesis;Prader-Willi and Angelman Syndrome (Consensus)

Recessive Scores

• pRec: 0.606

Haploinsufficiency Scores

• pHI: 0.831
• hipred: Y
• hipred_score: 0.735
• ghis: 0.463

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Msx1
• Phenotype: endocrine/exocrine gland 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); homeostasis/metabolism phenotype; craniofacial phenotype; muscle 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); 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); 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; embryo phenotype; skeleton phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: msx1a
• Affected structure: ceratobranchial cartilage
• Phenotype tag: abnormal
• Phenotype quality: shortened

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;cell morphogenesis;in utero embryonic development;epithelial to mesenchymal transition involved in endocardial cushion formation;muscle organ development;negative regulation of cell population proliferation;anterior/posterior pattern specification;mesenchymal cell proliferation;pituitary gland development;signal transduction involved in regulation of gene expression;negative regulation of cell growth;positive regulation of BMP signaling pathway;midbrain development;protein localization to nucleus;embryonic forelimb morphogenesis;embryonic hindlimb morphogenesis;embryonic nail plate morphogenesis;middle ear morphogenesis;odontogenesis of dentin-containing tooth;regulation of odontogenesis;negative regulation of apoptotic process;positive regulation of DNA damage response, signal transduction by p53 class mediator;positive regulation of transcription by RNA polymerase II;embryonic morphogenesis;stem cell differentiation;protein stabilization;negative regulation of striated muscle cell differentiation;roof of mouth development;face morphogenesis;bone morphogenesis;cartilage morphogenesis;mammary gland epithelium development;BMP signaling pathway involved in heart development;cellular response to nicotine;activation of meiosis;positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator;negative regulation of transcription regulatory region DNA binding;positive regulation of mesenchymal cell apoptotic process
• Cellular component: nucleus;nucleoplasm
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;p53 binding;enhancer binding