ALX4

ALX homeobox 4, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 11:44260439-44310139

Previous symbols: [ "PFM2" ]

Links

ENSG00000052850 ∙ NCBI:60529 ∙ OMIM:605420 ∙ HGNC:450 ∙ Uniprot:Q9H161 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• frontonasal dysplasia with alopecia and genital anomaly (Definitive), mode of inheritance: AR
• parietal foramina 2 (Definitive), mode of inheritance: AD
• parietal foramina 2 (Strong), mode of inheritance: AD
• frontonasal dysplasia with alopecia and genital anomaly (Strong), mode of inheritance: AR
• parietal foramina 2 (Moderate), mode of inheritance: AD
• frontonasal dysplasia with alopecia and genital anomaly (Moderate), mode of inheritance: AR
• parietal foramina (Supportive), mode of inheritance: AD
• frontonasal dysplasia with alopecia and genital anomaly (Supportive), mode of inheritance: AR
• frontonasal dysplasia with alopecia and genital anomaly (Strong), mode of inheritance: AR
• parietal foramina 2 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parietal foramina 2; Frontonasal dysplasia 2	AD/AR	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; Dermatologic; Musculoskeletal; Neurologic	11106354; 11137991; 16319823; 18541970; 19692347; 20301307; 22140057; 22829454; 23401352; 24668755; 24764194
Variants may contribute to nonsyndromic craniosynostosis

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALX4 gene.

• Parietal foramina 2 (162 variants)
• not provided (81 variants)
• Inborn genetic diseases (20 variants)
• Frontonasal dysplasia with alopecia and genital anomaly (12 variants)
• not specified (5 variants)
• Cranium bifidum occultum (5 variants)
• Frontonasal dysplasia with alopecia and genital anomaly;Craniosynostosis 5, susceptibility to;Parietal foramina 2 (2 variants)
• ALX4-related condition (1 variants)
• Optic nerve glioma (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALX4 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			7	15	7	29
missense	1		40	5	5	51
nonsense	2		2			4
start loss			1			1
frameshift		4				4
inframe indel			2		1	3
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			62	22	66	150
Total	3	4	114	42	79

Highest pathogenic variant AF is 0.0000131

Variants in ALX4

This is a list of pathogenic ClinVar variants found in the ALX4 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-44260749-G-A		Parietal foramina 2	Benign (Jan 13, 2018)
11-44260760-A-G		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44260855-G-A		Parietal foramina 2	Benign (Jan 13, 2018)
11-44260866-A-T		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44260905-G-C		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44261029-C-G		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44261049-C-T		Parietal foramina 2	Likely benign (Jan 12, 2018)
11-44261081-T-C		Parietal foramina 2	Benign (Jan 13, 2018)
11-44261085-A-G		Parietal foramina 2	Benign (Jan 12, 2018)
11-44261093-ATTTTTT-A		Cranium bifidum occultum	Uncertain significance (Jun 14, 2016)
11-44261228-A-C		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44261258-G-C		Parietal foramina 2	Benign (Jan 12, 2018)
11-44261277-G-A		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44261301-A-G		Parietal foramina 2	Uncertain significance (Mar 16, 2018)
11-44261348-A-T		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44261449-C-A		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44261449-C-T		Parietal foramina 2	Benign (Jan 13, 2018)
11-44261472-C-T		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44261473-G-A		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44261595-C-T		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44261613-G-C		Parietal foramina 2	Uncertain significance (Jan 13, 2018)
11-44261634-C-T		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44261688-G-A		Parietal foramina 2	Benign (Jan 12, 2018)
11-44261720-C-T		Parietal foramina 2	Uncertain significance (Jan 12, 2018)
11-44261731-C-T		Parietal foramina 2	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALX4	protein_coding	protein_coding	ENST00000329255	4	49723

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.357	0.642	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.821	213	249	0.854	0.0000147	2615
Missense in Polyphen		84	104.53	0.80357		1030
Synonymous	-1.53	128	108	1.19	0.00000653	812
Loss of Function	3.01	4	17.6	0.227	9.99e-7	163

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000308	0.000246
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000416	0.0000352
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000653	0.0000653
Other	0.000349	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor involved in skull and limb development. Plays an essential role in craniofacial development, skin and hair follicle development. {ECO:0000269|PubMed:19692347}.
• Disease: DISEASE: Frontonasal dysplasia 2 (FND2) [MIM:613451]: The term frontonasal dysplasia describes an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. {ECO:0000269|PubMed:19692347}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Potocki-Shaffer syndrome (POSHS) [MIM:601224]: A syndrome characterized by foramina parietalia permagna, multiple exostoses, and craniofacial dysostosis and mental retardation in some cases. {ECO:0000305|PubMed:11017806, ECO:0000305|PubMed:11903336}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Craniosynostosis 5 (CRS5) [MIM:615529]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:22829454}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.216

Intolerance Scores

• loftool: 0.155
• rvis_EVS: -0.45
• rvis_percentile_EVS: 24.33

Haploinsufficiency Scores

• pHI: 0.784
• hipred: Y
• hipred_score: 0.783
• ghis: 0.468

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.946

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Alx4
• Phenotype: skeleton phenotype; vision/eye phenotype; digestive/alimentary phenotype; limbs/digits/tail 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); 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; craniofacial phenotype; muscle 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)

Gene ontology

• Biological process: skeletal system development;hair follicle development;muscle organ development;post-embryonic development;anterior/posterior pattern specification;embryonic forelimb morphogenesis;embryonic hindlimb morphogenesis;embryonic digit morphogenesis;regulation of apoptotic process;positive regulation of transcription by RNA polymerase II;digestive tract development;embryonic skeletal system morphogenesis;roof of mouth development
• Cellular component: nucleus;transcription factor complex
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;protein heterodimerization activity;HMG box domain binding