HS6ST1

heparan sulfate 6-O-sulfotransferase 1, the group of Sulfotransferases, membrane bound

Basic information

Region (hg38): 2:128236716-128318868

Previous symbols: [ "HS6ST" ]

Links

ENSG00000136720 ∙ NCBI:9394 ∙ OMIM:604846 ∙ HGNC:5201 ∙ Uniprot:O60243 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism 15 with or without anosmia (Limited), mode of inheritance: AD
• hypogonadotropic hypogonadism 15 with or without anosmia (Limited), mode of inheritance: Unknown
• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 15 with or without anosmia (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 15, with or without anosmia	AD/AR/Digenic/Multigenic	Endocrine	Surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to male fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required	Endocrine; Musculoskeletal; Neurologic	21700882; 23643382
Relatively complex models of inheritance such as digenic inheritance and interaction with other related loci (eg, FGF8-network-associated genes) have been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HS6ST1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HS6ST1 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			3	23	8	34
missense			64	5	3	72
nonsense						0
start loss			1			1
frameshift						0
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				7	11	18
Total	0	0	70	35	22

Variants in HS6ST1

This is a list of pathogenic ClinVar variants found in the HS6ST1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-128267822-G-A			Likely benign (Nov 20, 2018)
2-128267829-TC-T			Benign (Oct 24, 2018)
2-128267894-C-G			Likely benign (Apr 24, 2019)
2-128268045-T-C			Benign (Oct 21, 2018)
2-128268131-C-G			Benign (Aug 30, 2018)
2-128268180-G-C			Uncertain significance (Aug 16, 2022)
2-128268185-T-C			Uncertain significance (Jan 14, 2021)
2-128268188-T-C		Hypogonadotropic hypogonadism 15 with anosmia	risk factor (Jul 12, 2011)
2-128268197-C-T		not specified	Uncertain significance (Oct 26, 2021)
2-128268198-G-A			Likely benign (Nov 14, 2023)
2-128268202-G-A		not specified	Uncertain significance (Jul 14, 2024)
2-128268204-C-T		See cases	Uncertain significance (Jun 23, 2022)
2-128268205-A-G			Uncertain significance (Feb 25, 2023)
2-128268207-G-A			Likely benign (Nov 14, 2023)
2-128268212-C-A			Uncertain significance (Nov 19, 2023)
2-128268214-G-A		not specified	Uncertain significance (Jul 25, 2023)
2-128268219-G-A			Likely benign (Apr 26, 2024)
2-128268221-C-T			Benign (Mar 14, 2023)
2-128268222-G-A			Likely benign (Dec 16, 2024)
2-128268235-G-A		not specified	Uncertain significance (Oct 01, 2024)
2-128268253-C-T		not specified	Uncertain significance (Dec 13, 2022)
2-128268254-G-A		HYPOGONADOTROPIC HYPOGONADISM 15 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO • Hypogonadotropic hypogonadism 7 with or without anosmia • Hypogonadotropic hypogonadism 15 with or without anosmia • not specified • HS6ST1-related disorder	Benign/Likely benign (Aug 06, 2024)
2-128268265-C-T		not specified	Uncertain significance (Mar 07, 2023)
2-128268266-G-A		not specified	Uncertain significance (May 07, 2024)
2-128268273-G-A			Likely benign (Sep 18, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HS6ST1	protein_coding	protein_coding	ENST00000259241	2	81862

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.923	0.0764	122835	0	1477	124312	0.00596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.92	178	266	0.668	0.0000191	2610
Missense in Polyphen		83	134.95	0.61503		1376
Synonymous	-0.845	135	123	1.10	0.00000888	830
Loss of Function	3.03	1	12.6	0.0792	5.52e-7	137

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00793	0.00782
Ashkenazi Jewish	0.00522	0.00499
East Asian	0.0000559	0.0000557
Finnish	0.00634	0.00600
European (Non-Finnish)	0.00868	0.00809
Middle Eastern	0.0000559	0.0000557
South Asian	0.00408	0.00396
Other	0.00877	0.00830

dbNSFP

Source: dbNSFP

• Function: FUNCTION: 6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate. Critical for normal neuronal development where it may play a role in neuron branching. May also play a role in limb development. May prefer iduronic acid. {ECO:0000269|PubMed:21700882}.
• Disease: DISEASE: Hypogonadotropic hypogonadism 15 with or without anosmia (HH15) [MIM:614880]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:21700882, ECO:0000269|PubMed:25077900}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.
• Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human);Metapathway biotransformation Phase I and II;Metabolism of carbohydrates;HS-GAG biosynthesis;Heparan sulfate/heparin (HS-GAG) metabolism;Glycosaminoglycan metabolism;heparan sulfate biosynthesis (late stages);heparan sulfate biosynthesis;Metabolism (Consensus)

Recessive Scores

• pRec: 0.156

Haploinsufficiency Scores

• pHI: 0.465
• hipred: Y
• hipred_score: 0.728
• ghis: 0.619

Essentials

• essential_gene_CRISPR: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.323

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hs6st1
• 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); 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); respiratory system phenotype; embryo phenotype; skeleton phenotype; vision/eye phenotype; limbs/digits/tail phenotype; growth/size/body region phenotype; cellular phenotype

Gene ontology

• Biological process: angiogenesis;glycosaminoglycan biosynthetic process;heparan sulfate proteoglycan biosynthetic process, enzymatic modification;lung alveolus development;neuron development;labyrinthine layer blood vessel development
• Cellular component: Golgi membrane;integral component of plasma membrane
• Molecular function: sulfotransferase activity;heparan sulfate 6-O-sulfotransferase activity