DLX5

distal-less homeobox 5, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 7:97020396-97024950

Links

ENSG00000105880 ∙ NCBI:1749 ∙ OMIM:600028 ∙ HGNC:2918 ∙ Uniprot:P56178 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• split hand-foot malformation 1 with sensorineural hearing loss (Limited), mode of inheritance: AR
• split hand-foot malformation (Supportive), mode of inheritance: AD
• split hand-foot malformation 1 with sensorineural hearing loss (Supportive), mode of inheritance: AR
• split hand-foot malformation 1 with sensorineural hearing loss (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Split-hand/foot malformation 1; Split-hand/foot malformation 1 with sensorineural hearing loss	AD/AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Dental; Musculoskeletal	22121204; 24496061; 25196357
The condition may be recognizable, but deafness may not be recognized as a component feature

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DLX5 gene.

• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DLX5 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			1	6	2	9
missense		1	18	3		22
nonsense		1				1
start loss						0
frameshift	1		2			3
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region						0
non coding				5	4	9
Total	1	2	22	14	6

Highest pathogenic variant AF is 0.00000657

Variants in DLX5

This is a list of pathogenic ClinVar variants found in the DLX5 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-97020572-A-AG			Benign (Aug 15, 2019)
7-97020766-CG-C		Split hand-foot malformation 1	Uncertain significance (Oct 08, 2024)
7-97020782-C-A		Inborn genetic diseases	Uncertain significance (Dec 31, 2023)
7-97020792-G-A			Uncertain significance (Sep 05, 2023)
7-97020807-T-C		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
7-97020894-G-T		Inborn genetic diseases	Uncertain significance (Oct 13, 2023)
7-97020904-G-A			Benign (Nov 27, 2023)
7-97020904-G-T			Benign/Likely benign (Jun 01, 2024)
7-97020910-C-G		DLX5-related disorder	Likely benign (May 20, 2019)
7-97020914-C-T			Likely benign (Jun 08, 2018)
7-97020937-C-A			Likely benign (Dec 03, 2022)
7-97020984-T-TGG		DLX5-related disorder	Uncertain significance (Jun 06, 2023)
7-97020998-G-A			Uncertain significance (Aug 19, 2023)
7-97020999-G-T			Uncertain significance (Jan 12, 2022)
7-97021019-A-C		Inborn genetic diseases	Uncertain significance (Mar 04, 2024)
7-97021026-T-G		Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 12, 2022)
7-97021035-TG-T			Uncertain significance (Feb 08, 2023)
7-97021048-C-A		Split hand-foot malformation 1	Pathogenic (Sep 01, 2014)
7-97021057-G-A			Likely benign (Sep 01, 2022)
7-97021066-C-T		DLX5-related disorder	Likely pathogenic (Aug 13, 2024)
7-97021075-G-A		DLX5-related disorder	Benign (Nov 28, 2023)
7-97021958-G-A			Likely benign (Dec 09, 2018)
7-97022094-A-G			Benign (Oct 16, 2018)
7-97022165-C-T			Likely benign (Apr 14, 2023)
7-97022192-T-G		Split hand-foot malformation 1 with sensorineural hearing loss	Pathogenic (Jan 01, 2012)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DLX5	protein_coding	protein_coding	ENST00000222598	3	4706

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.218	0.774	125738	0	10	125748	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0387	166	167	0.992	0.00000759	1871
Missense in Polyphen		56	65.954	0.84907		711
Synonymous	-1.29	90	75.7	1.19	0.00000369	592
Loss of Function	2.30	3	11.4	0.263	4.86e-7	133

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000616	0.0000615
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional factor involved in bone development. Acts as an immediate early BMP-responsive transcriptional activator essential for osteoblast differentiation. Stimulates ALPL promoter activity in a RUNX2-independent manner during osteoblast differentiation. Stimulates SP7 promoter activity during osteoblast differentiation. Promotes cell proliferation by up-regulating MYC promoter activity. Involved as a positive regulator of both chondrogenesis and chondrocyte hypertrophy in the endochondral skeleton. Binds to the homeodomain-response element of the ALPL and SP7 promoter. Binds to the MYC promoter. Requires the 5'-TAATTA-3' consensus sequence for DNA-binding. {ECO:0000269|PubMed:19497851}.
• Disease: DISEASE: Split-hand/foot malformation 1 with sensorineural hearing loss, autosomal recessive (SHFM1D) [MIM:220600]: A disease characterized by the association of split-hand/foot malformation with deafness. Split-hand/foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients have been found to have mental retardation, ectodermal and craniofacial findings, and orofacial clefting. {ECO:0000269|PubMed:22121204}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Neural Crest Differentiation;MECP2 and Associated Rett Syndrome;Prader-Willi and Angelman Syndrome;Transcriptional regulation by RUNX2;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Validated transcriptional targets of deltaNp63 isoforms;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.323

Intolerance Scores

• loftool: 0.0750
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.75

Haploinsufficiency Scores

• pHI: 0.919
• hipred: Y
• hipred_score: 0.851
• ghis: 0.571

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.942

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dlx5
• Phenotype: skeleton phenotype; digestive/alimentary 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); 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); normal phenotype; embryo phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); taste/olfaction phenotype

Zebrafish Information Network

• Gene name: dlx5a
• Affected structure: olfactory bulb glomerulus
• Phenotype tag: abnormal
• Phenotype quality: aplastic/hypoplastic

Gene ontology

• Biological process: skeletal system development;osteoblast differentiation;endochondral ossification;regulation of transcription by RNA polymerase II;nervous system development;cell population proliferation;olfactory bulb interneuron differentiation;cell differentiation;embryonic limb morphogenesis;BMP signaling pathway;epithelial cell differentiation;inner ear morphogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;anatomical structure formation involved in morphogenesis;positive regulation of epithelial cell proliferation;roof of mouth development;olfactory pit development;face morphogenesis;cellular response to BMP stimulus;positive regulation of canonical Wnt signaling pathway;interneuron axon guidance;positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus
• Cellular component: nuclear chromatin;nucleus;cytoplasm
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;sequence-specific DNA binding;transcription regulatory region DNA binding;HMG box domain binding