HESX1

HESX homeobox 1, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 3:57197837-57227606

Links

ENSG00000163666 ∙ NCBI:8820 ∙ OMIM:601802 ∙ HGNC:4877 ∙ Uniprot:Q9UBX0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• septooptic dysplasia (Strong), mode of inheritance: AR
• septooptic dysplasia (Strong), mode of inheritance: AD
• septooptic dysplasia (Strong), mode of inheritance: AD
• septooptic dysplasia (Supportive), mode of inheritance: AD
• Kallmann syndrome (Supportive), mode of inheritance: AD
• combined pituitary hormone deficiencies, genetic form (Supportive), mode of inheritance: AD
• pituitary stalk interruption syndrome (Supportive), mode of inheritance: AD
• hypothyroidism due to deficient transcription factors involved in pituitary development or function (Supportive), mode of inheritance: AD
• septooptic dysplasia (Strong), mode of inheritance: AR
• septooptic dysplasia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pituitary hormone deficiency, combined; Septooptic dysplasia	AD/AR	Endocrine	Some individuals may have life-threatening adrenal insufficiency as well as additional endocrine insufficiency, and early recognition and immediate and long-term treatment can be beneficial	Endocrine; Neurologic; Ophthalmologic	8696006; 9620767; 11136712; 14561704; 12519827; 16940453; 22145475

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HESX1 gene.

• Growth hormone deficiency with pituitary anomalies;Septo-optic dysplasia sequence (32 variants)
• not provided (27 variants)
• Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies (27 variants)
• Septo-optic dysplasia sequence (25 variants)
• Inborn genetic diseases (10 variants)
• Combined Pituitary Hormone Deficiency, Dominant/Recessive (7 variants)
• not specified (6 variants)
• Pituitary hormone deficiency, combined, 1 (4 variants)
• Growth hormone deficiency with pituitary anomalies (1 variants)
• Septooptic dysplasia, mild (1 variants)
• HESX1-related condition (1 variants)
• Amenorrhea (1 variants)
• Pituitary hormone deficiency, combined 5 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HESX1 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	12		13
missense	1		37	1		39
nonsense	4	2				6
start loss						0
frameshift	4	1	1			6
inframe indel						0
splice donor/acceptor (+/-2bp)		2				2
splice region			2	2	2	6
non coding			7	4	3	14
Total	9	5	46	17	3

Highest pathogenic variant AF is 0.0000263

Variants in HESX1

This is a list of pathogenic ClinVar variants found in the HESX1 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-57198005-A-T		Combined Pituitary Hormone Deficiency, Dominant/Recessive • Septo-optic dysplasia sequence	Uncertain significance (Jan 13, 2018)
3-57198149-C-T		Septo-optic dysplasia sequence	Uncertain significance (Jan 12, 2018)
3-57198196-T-C		HESX1-related disorder	Likely benign (Jan 24, 2023)
3-57198210-T-A		Inborn genetic diseases	Uncertain significance (Jun 13, 2023)
3-57198214-T-C		Growth hormone deficiency with pituitary anomalies • Septo-optic dysplasia sequence • Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies • Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 15, 2023)
3-57198229-TC-T		Septo-optic dysplasia sequence	Pathogenic (Oct 01, 2003)
3-57198230-C-T		not specified • Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies • Septo-optic dysplasia sequence	Conflicting classifications of pathogenicity (Jan 29, 2024)
3-57198238-G-A		Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Likely benign (Feb 12, 2020)
3-57198242-CTG-C		not specified	Conflicting classifications of pathogenicity (Oct 10, 2018)
3-57198246-G-A		Septooptic dysplasia, mild • Growth hormone deficiency with pituitary anomalies;Septo-optic dysplasia sequence	Uncertain significance (Aug 17, 2023)
3-57198254-A-C			Uncertain significance (May 02, 2022)
3-57198257-G-A		Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Likely benign (Apr 11, 2023)
3-57198276-C-T		Inborn genetic diseases • Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Conflicting classifications of pathogenicity (Jan 06, 2024)
3-57198277-G-A		Septo-optic dysplasia sequence	Pathogenic (Jun 01, 1998)
3-57198280-G-A		Septo-optic dysplasia sequence • Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Conflicting classifications of pathogenicity (Sep 17, 2023)
3-57198298-A-G		Growth hormone deficiency with pituitary anomalies;Septo-optic dysplasia sequence • Inborn genetic diseases	Uncertain significance (Jan 02, 2023)
3-57198302-T-C		Septo-optic dysplasia sequence	Likely benign (May 28, 2019)
3-57198305-A-T		Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Likely benign (Jul 10, 2023)
3-57198373-A-G		Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Likely benign (Apr 24, 2023)
3-57198376-A-G		Septo-optic dysplasia sequence;Growth hormone deficiency with pituitary anomalies	Likely benign (Jun 16, 2022)
3-57198398-CTG-C		Pituitary hormone deficiency, combined 5	Pathogenic (Nov 01, 2006)
3-57198400-G-C		Septo-optic dysplasia sequence	Uncertain significance (-)
3-57198405-C-T		Growth hormone deficiency with pituitary anomalies	Pathogenic (Feb 01, 2007)
3-57198411-G-T		Growth hormone deficiency with pituitary anomalies;Septo-optic dysplasia sequence	Uncertain significance (Jun 10, 2023)
3-57198419-T-G		Growth hormone deficiency with pituitary anomalies;Septo-optic dysplasia sequence	Uncertain significance (Jun 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HESX1	protein_coding	protein_coding	ENST00000295934	4	28606

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000797	0.791	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.157	99	94.7	1.05	0.00000491	1205
Missense in Polyphen		21	24.55	0.8554		310
Synonymous	0.680	31	36.2	0.856	0.00000195	339
Loss of Function	1.07	6	9.56	0.628	4.94e-7	124

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000905	0.0000905
Ashkenazi Jewish	0.000496	0.000496
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000882	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.0000981	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland. Possible transcriptional repressor. Binds to the palindromic PIII sequence, 5'-AGCTTGAGTCTAATTGAATTAACTGTAC-3'. HESX1 and PROP1 bind as heterodimers on this palindromic site, and, in vitro, HESX1 can antagonize PROP1 activation. {ECO:0000250|UniProtKB:Q61658, ECO:0000269|PubMed:26781211}.
• Disease: DISEASE: Septooptic dysplasia (SOD) [MIM:182230]: A clinically heterogeneous disorder defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia with panhypopopituitarism, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum. {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:9620767}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Growth hormone deficiency with pituitary anomalies (GHDPA) [MIM:182230]: A disease characterized by low or absent growth hormone levels, in the presence of a hypoplastic anterior pituitary lobe and ectopic or absent posterior pituitary lobe. {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:17148560}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pituitary hormone deficiency, combined, 5 (CPHD5) [MIM:182230]: Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD5 is characterized by complete or partial deficiencies of growth hormone, thyroid- stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:14561704, ECO:0000269|PubMed:26781211}. 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);Ectoderm Differentiation (Consensus)

Recessive Scores

• pRec: 0.194

Intolerance Scores

• loftool: 0.470
• rvis_EVS: 0.19
• rvis_percentile_EVS: 66.82

Haploinsufficiency Scores

• pHI: 0.598
• hipred: Y
• hipred_score: 0.568
• ghis: 0.476

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.571

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hesx1
• 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); normal phenotype; respiratory system phenotype; embryo phenotype; vision/eye 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); taste/olfaction phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; craniofacial phenotype

Gene ontology

• Biological process: regulation of transcription by RNA polymerase II;brain development;pituitary gland development
• Cellular component: nucleus
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;protein binding