BHLHA9

basic helix-loop-helix family member a9, the group of Basic helix-loop-helix proteins

Basic information

Region (hg38): 17:1270444-1271815

Links

ENSG00000205899 ∙ NCBI:727857 ∙ OMIM:615416 ∙ HGNC:35126 ∙ Uniprot:Q7RTU4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mesoaxial synostotic syndactyly with phalangeal reduction (Strong), mode of inheritance: AR
• mesoaxial synostotic syndactyly with phalangeal reduction (Supportive), mode of inheritance: AR
• split-hand/foot malformation with long bone deficiency 1 (Limited), mode of inheritance: Unknown
• mesoaxial synostotic syndactyly with phalangeal reduction (Strong), mode of inheritance: AR
• Camptosynpolydactyly, complex (Limited), mode of inheritance: AR
• tibial aplasia-ectrodactyly syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Camptopolysyndactyly, complex; Syndactyly, mesoaxial synostotic, with phalangeal reduction	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	Musculoskeletal	9783716; 10096595; 15039974; 15779011; 25466284; 27041388

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BHLHA9 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BHLHA9 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				14	1	15
missense		3	33	3		39
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				5	1	6
Total	0	3	33	22	2

Variants in BHLHA9

This is a list of pathogenic ClinVar variants found in the BHLHA9 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-1270496-A-G			Benign (Nov 10, 2018)
17-1270538-G-A			Likely benign (Mar 14, 2020)
17-1270595-C-A		Inborn genetic diseases	Uncertain significance (Nov 08, 2022)
17-1270596-G-A		BHLHA9-related disorder	Likely benign (Mar 15, 2024)
17-1270605-G-C		Inborn genetic diseases	Uncertain significance (Dec 03, 2024)
17-1270605-G-T		Inborn genetic diseases	Uncertain significance (Jul 20, 2022)
17-1270607-G-A		Inborn genetic diseases	Uncertain significance (Nov 13, 2024)
17-1270637-G-A		Inborn genetic diseases	Uncertain significance (Sep 25, 2024)
17-1270679-C-A		not specified	Benign/Likely benign (Dec 04, 2024)
17-1270689-T-G			Likely benign (Oct 15, 2024)
17-1270703-G-A		Inborn genetic diseases	Uncertain significance (Mar 16, 2024)
17-1270703-G-T			Uncertain significance (Jun 24, 2019)
17-1270716-G-A			Likely benign (Dec 04, 2024)
17-1270718-C-T			Uncertain significance (Mar 24, 2021)
17-1270720-G-A		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 28, 2025)
17-1270763-G-T		Inborn genetic diseases	Uncertain significance (Jan 22, 2025)
17-1270774-A-G		Mesoaxial synostotic syndactyly with phalangeal reduction	Pathogenic (Dec 04, 2014)
17-1270781-G-C		Mesoaxial synostotic syndactyly with phalangeal reduction	Likely pathogenic (Jul 22, 2022)
17-1270781-G-T		Mesoaxial synostotic syndactyly with phalangeal reduction	Likely pathogenic (Mar 29, 2024)
17-1270783-GA-TT		Camptosynpolydactyly, complex	Likely pathogenic (Jan 01, 2015)
17-1270787-G-T		Mesoaxial synostotic syndactyly with phalangeal reduction	Pathogenic (Dec 04, 2014)
17-1270800-A-G		Camptosynpolydactyly, complex • Mesoaxial synostotic syndactyly with phalangeal reduction • BHLHA9-related disorder	Benign (Jan 29, 2025)
17-1270809-C-T			Likely benign (May 26, 2021)
17-1270814-C-G			Uncertain significance (Oct 27, 2019)
17-1270814-C-T			Uncertain significance (Nov 21, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BHLHA9	protein_coding	protein_coding	ENST00000391429	1	902

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.296	0.501	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0222	14	14.2	0.983	0.00000119	1417
Missense in Polyphen		2	1.6851	1.1869		154
Synonymous	-1.16	11	7.09	1.55	5.68e-7	586
Loss of Function	0.352	0	0.144	0.00	5.99e-9	20

LoF frequencies by population

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

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor, which play a role in limb development. Is an essential player in the regulatory network governing transcription of genes implicated in limb morphogenesis. {ECO:0000269|PubMed:22147889, ECO:0000269|PubMed:25466284}.
• Disease: DISEASE: Split-hand/foot malformation with long bone deficiency 3 (SHFLD3) [MIM:612576]: A disease characterized by the association of split-hand/foot malformation with long bone deficiency involving the tibia and fibula. Split-hand/foot malformation is a limb malformation involving the central rays of the autopod. Phenotypic expression is extremely variable between and within families, and even between limbs of a single patient, ranging from syndactyly and oligodactyly to the most severe monodactyly with only a single phalanx. Limb features include median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. {ECO:0000269|PubMed:22147889}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. A copy number variation (CNV) resulting in BHLHA9 duplications is a necessary but not sufficient susceptibility factor for Split-hand/foot malformation with long bone deficiency, a highly variable phenotype with reduced penetrance, particularly in females (PubMed:22147889). {ECO:0000269|PubMed:22147889}.; DISEASE: Syndactyly, mesoaxial synostotic, with phalangeal reduction (MSSD) [MIM:609432]: An autosomal recessive, non- syndromic digit anomaly characterized by mesoaxial osseous synostosis at a metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes. {ECO:0000269|PubMed:25466284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Camptosynpolydactyly, complex (CCSPD) [MIM:607539]: An autosomal recessive disorder characterized by hand and foot deformities consisting of polydactyly with digits arising from the dorsum of hands, syn- and camptodactyly of some fingers, soft tissue syndactyly of first and second toes, and dysplastic nails. {ECO:0000269|PubMed:27041388}. Note=The disease may be caused by mutations affecting the gene represented in this entry.

Haploinsufficiency Scores

• ghis: 0.407

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.128

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Bhlha9
• Phenotype: limbs/digits/tail phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: bhlha9
• Affected structure: pectoral fin
• Phenotype tag: abnormal
• Phenotype quality: truncated

Gene ontology

• Biological process: regulation of transcription by RNA polymerase II;multicellular organism development
• Cellular component: nucleus;cytoplasm
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;protein binding;protein heterodimerization activity