HOXD13

homeobox D13, the group of HOXL subclass homeoboxes

Basic information

Region (hg38): 2:176092721-176095944

Previous symbols: [ "HOX4I", "SPD" ]

Links

ENSG00000128714 ∙ NCBI:3239 ∙ OMIM:142989 ∙ HGNC:5136 ∙ Uniprot:P35453 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• brachydactyly-syndactyly syndrome (Definitive), mode of inheritance: AD
• brachydactyly type E (Supportive), mode of inheritance: AD
• syndactyly type 5 (Supportive), mode of inheritance: AD
• brachydactyly-syndactyly syndrome (Supportive), mode of inheritance: AD
• synpolydactyly type 1 (Supportive), mode of inheritance: AD
• brachydactyly-syndactyly syndrome (Strong), mode of inheritance: AD
• synpolydactyly type 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Brachydactyly-syndactyly syndrome; Brachydactyly, type D; Brachydactyly, type E1; Syndactyly, type V; Synopolydactyly, type I, Synopolydactyly, type II; Synopolydactyly with clefting, autosomal recessive	AD/AR	Renal	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	7666393; 8817328; 8614804; 8933344; 9758628; 11778160; 12116248; 12649808; 12900906; 16222680; 17236141; 19006232; 18177473; 19060004; 20974300; 21814222; 22233338; 22373878; 22374128; 22406499; 22473151
The condition has also been implicated in VACTERL association (AD), but the pathogenesis is unclear

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HOXD13 gene.

• not provided (6 variants)
• Synpolydactyly type 1 (3 variants)
• HOXD13-related disorder (2 variants)
• Syndactyly type 5 (1 variants)
• Synpolydactyly type 1;Syndactyly type 5;Brachydactyly type E1;Brachydactyly-syndactyly syndrome;Brachydactyly type D (1 variants)
• Brachydactyly type E1;Brachydactyly type D;Syndactyly type 5;Synpolydactyly type 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HOXD13 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	5	4	10
missense		2	40	4		46
nonsense		1				1
start loss						0
frameshift	5	1				6
inframe indel	5		7	6	1	19
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				3	9	12
Total	10	4	48	18	14

Variants in HOXD13

This is a list of pathogenic ClinVar variants found in the HOXD13 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-176092791-C-A			Likely benign (Jan 13, 2019)
2-176092852-G-C			Benign (Mar 03, 2015)
2-176092896-C-A			Uncertain significance (Jun 23, 2023)
2-176092908-C-G			Uncertain significance (Nov 30, 2023)
2-176092922-G-C		Synpolydactyly type 1	Conflicting classifications of pathogenicity (Sep 21, 2022)
2-176092931-C-T		not specified	Benign/Likely benign (Dec 12, 2023)
2-176092946-C-G		Inborn genetic diseases	Uncertain significance (Jul 14, 2021)
2-176092965-TTCC-T			Uncertain significance (Apr 11, 2019)
2-176092982-TGGC-T		HOXD13-related disorder	Likely benign (May 31, 2022)
2-176092982-T-TGGC			Uncertain significance (Nov 12, 2023)
2-176093007-G-C		Inborn genetic diseases	Uncertain significance (Feb 22, 2024)
2-176093015-G-T			Uncertain significance (Oct 12, 2023)
2-176093025-C-T			Conflicting classifications of pathogenicity (Nov 14, 2023)
2-176093048-A-T			Uncertain significance (Dec 23, 2021)
2-176093050-T-A		Inborn genetic diseases	Uncertain significance (Jun 17, 2024)
2-176093052-GGGGCGGGCGGCGGCGGCGGCA-G		VACTERL association	Uncertain significance (Dec 15, 2008)
2-176093054-G-C			Uncertain significance (Jul 19, 2022)
2-176093057-G-A			Uncertain significance (Aug 04, 2023)
2-176093057-GGGC-G		HOXD13-related disorder	Likely benign (Apr 13, 2020)
2-176093057-GGGCGGCGGCGGC-G			Uncertain significance (Feb 09, 2023)
2-176093057-GGGCGGCGGCGGCGGCAGCGGCGGCTGC-G			Uncertain significance (Aug 16, 2022)
2-176093057-G-GGGC		Brachydactyly-syndactyly syndrome	Likely benign (Jan 27, 2022)
2-176093057-G-GGGCGGCGGC			Uncertain significance (Sep 16, 2018)
2-176093057-G-GGGCGGCGGCGGCGGCAGCGGCGGCTGC		HOXD13-related disorder	Pathogenic (Nov 27, 2023)
2-176093058-GGCGGCGGCGGCGGCAGCGGCGGCT-G		HOXD13-related disorder	Likely benign (Jun 01, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HOXD13	protein_coding	protein_coding	ENST00000392539	2	3048

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00861	0.940	125717	0	30	125747	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0420	159	161	0.991	0.00000751	2148
Missense in Polyphen		32	42.236	0.75765		521
Synonymous	-0.961	80	69.8	1.15	0.00000354	738
Loss of Function	1.69	5	11.0	0.453	4.87e-7	124

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000714	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.000697	0.000693
European (Non-Finnish)	0.0000914	0.0000791
Middle Eastern	0.000109	0.000109
South Asian	0.0000327	0.0000327
Other	0.000335	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Sequence-specific transcription factor that binds gene promoters and activates their transcription (PubMed:24789103). Part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis (By similarity). {ECO:0000250|UniProtKB:P24344, ECO:0000269|PubMed:24789103}.
• Disease: DISEASE: Synpolydactyly 1 (SPD1) [MIM:186000]: Limb malformation that shows a characteristic manifestation in both hands and feet. This condition is inherited as an autosomal dominant trait with reduced penetrance. {ECO:0000269|PubMed:12414828, ECO:0000269|PubMed:16222680, ECO:0000269|PubMed:24789103, ECO:0000269|PubMed:26581570, ECO:0000269|PubMed:8817328}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brachydactyly D (BDD) [MIM:113200]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type D is characterized by short and broad terminal phalanges of the thumbs and big toes. {ECO:0000269|PubMed:12649808}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Syndactyly 5 (SDTY5) [MIM:186300]: A form of syndactyly, a congenital anomaly of the hand or foot marked by persistence of the webbing between adjacent digits that are more or less completely attached. The characteristic finding in SDTY5 is the presence of an associated metacarpal and metatarsal fusion. The metacarpals and metatarsals most commonly fused are the 4th and 5th or the 3rd and 4th. Soft tissue syndactyly usually affects the 3rd and 4th fingers and the 2nd and 3rd toes. {ECO:0000269|PubMed:17236141}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brachydactyly-syndactyly syndrome (BDSD) [MIM:610713]: A disease characterized by generalized shortening of the hands and feet, broad and short distal phalanges of the thumbs, and cutaneous syndactyly of toes 2 and 3. The limb phenotypes observed in this syndrome overlap those of brachydactyly types A4, D, E and syndactyly type 1. {ECO:0000269|PubMed:17236141}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brachydactyly E1 (BDE1) [MIM:113300]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. Brachydactyly type E1 is characterized by shortening limited to fourth metacarpals and/or metatarsals. {ECO:0000269|PubMed:12649808, ECO:0000269|PubMed:24789103}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: VACTERL association (VACTERL) [MIM:192350]: VACTERL is an acronym for vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects. {ECO:0000269|PubMed:19006232}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Brachydactyly-syndactyly-oligodactyly syndrome (BDSDO) [MIM:610713]: A syndrome characterized by a complex brachydactyly- syndactyly-oligodactyly phenotype. Limb anomalies include reduced number of digits that are severely shortened, camptodactyly, syndactyly, absence of terminal phalanges of the thumbs, and absence of nails of the thumbs and toes. {ECO:0000269|PubMed:23995701}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.409

Intolerance Scores

• loftool: 0.163
• rvis_EVS: -0.1
• rvis_percentile_EVS: 46.49

Haploinsufficiency Scores

• pHI: 0.832
• hipred: Y
• hipred_score: 0.559
• ghis: 0.444

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.880

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hoxd13
• 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); reproductive system phenotype; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; limbs/digits/tail phenotype; digestive/alimentary phenotype; vision/eye 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); growth/size/body region phenotype; endocrine/exocrine gland phenotype; muscle phenotype

Gene ontology

• Biological process: skeletal system development;regulation of transcription, DNA-templated;transcription by RNA polymerase II;multicellular organism development;anterior/posterior pattern specification;male genitalia development;response to testosterone;regulation of cell population proliferation;embryonic digit morphogenesis;positive regulation of transcription by RNA polymerase II;embryonic hindgut morphogenesis;prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis;morphogenesis of an epithelial fold;branch elongation of an epithelium;regulation of branching involved in prostate gland morphogenesis
• Cellular component: nucleus
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;enhancer sequence-specific DNA binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;chromatin binding;DNA-binding transcription factor activity