HBS1L

Summary

HBS1L (HBS1 like translational GTPase, HGNC:4834) is a protein-coding gene on chromosome 6q23.3, encoding HBS1-like protein (Q9Y450). GTPase component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway.

This gene encodes a member of the GTP-binding elongation factor family. It is expressed in multiple tissues with the highest expression in heart and skeletal muscle. The intergenic region of this gene and the MYB gene has been identified to be a quantitative trait locus (QTL) controlling fetal hemoglobin level, and this region influnces erythrocyte, platelet, and monocyte counts as well as erythrocyte volume and hemoglobin content. DNA polymorphisms at this region associate with fetal hemoglobin levels and pain crises in sickle cell disease. A single nucleotide polymorphism in exon 1 of this gene is significantly associated with severity in beta-thalassemia/Hemoglobin E. Multiple alternatively spliced transcript variants encoding different protein isoforms have been found for this gene.

Source: NCBI Gene 10767 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinal disorder (Moderate, GenCC)
• GWAS associations: 173
• Clinical variants (ClinVar): 90 total
• Druggable target: yes
• MANE Select transcript: NM_006620

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4834
Approved symbol	HBS1L
Name	HBS1 like translational GTPase
Location	6q23.3
Locus type	gene with protein product
Status	Approved
Aliases	ERFS, HBS1, HSPC276, KIAA1038, DKFZp434g247, EF-1a, eRF3c
Ensembl gene	ENSG00000112339
Ensembl biotype	protein_coding
OMIM	612450
Entrez	10767

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 20 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000314674, ENST00000367820, ENST00000367822, ENST00000367826, ENST00000367837, ENST00000415177, ENST00000524715, ENST00000525067, ENST00000526100, ENST00000527005, ENST00000527507, ENST00000527578, ENST00000529169, ENST00000529641, ENST00000529882, ENST00000533274, ENST00000881131, ENST00000919570, ENST00000949311, ENST00000949312, ENST00000949313, ENST00000949314

RefSeq mRNA: 4 — MANE Select: NM_006620 NM_001145158, NM_001145207, NM_001363686, NM_006620

CCDS: CCDS47479, CCDS47480, CCDS5173, CCDS87443

Canonical transcript exons

ENST00000367837 — 18 exons

Exon	Start	End
ENSE00000764156	135039573	135039767
ENSE00000764158	135050582	135050647
ENSE00000919268	134997397	134997656
ENSE00001376601	135054649	135054822
ENSE00001632291	134960378	134965290
ENSE00003471947	135042001	135042126
ENSE00003499193	134969238	134969338
ENSE00003506575	134996777	134996942
ENSE00003516835	134982458	134982562
ENSE00003573789	134986736	134986810
ENSE00003574523	134966329	134966473
ENSE00003574550	135002734	135002842
ENSE00003588505	134987645	134987791
ENSE00003591167	134985341	134985409
ENSE00003600276	134978679	134978787
ENSE00003600727	134993758	134993875
ENSE00003670218	134986066	134986183
ENSE00003677813	134979178	134979268

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 97.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.0186 / max 952.8712, expressed in 1809 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75708	33.9875	1807
75709	1.5780	836
75707	0.3967	156
75710	0.0564	16

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.44	gold quality
muscle of leg	UBERON:0001383	96.65	gold quality
gastrocnemius	UBERON:0001388	96.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.90	gold quality
ventricular zone	UBERON:0003053	95.88	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.88	gold quality
islet of Langerhans	UBERON:0000006	95.56	gold quality
adrenal tissue	UBERON:0018303	95.38	gold quality
ganglionic eminence	UBERON:0004023	95.28	gold quality
tendon	UBERON:0000043	95.17	gold quality
cortical plate	UBERON:0005343	95.12	gold quality
colonic epithelium	UBERON:0000397	94.91	gold quality
stromal cell of endometrium	CL:0002255	94.82	gold quality
muscle organ	UBERON:0001630	94.79	gold quality
skeletal muscle organ	UBERON:0014892	94.79	gold quality
triceps brachii	UBERON:0001509	94.32	gold quality
spinal cord	UBERON:0002240	94.19	gold quality
corpus callosum	UBERON:0002336	93.62	gold quality
heart right ventricle	UBERON:0002080	93.45	gold quality
tendon of biceps brachii	UBERON:0008188	93.41	gold quality
gluteal muscle	UBERON:0002000	93.33	gold quality
biceps brachii	UBERON:0001507	93.20	gold quality
prefrontal cortex	UBERON:0000451	93.18	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.06	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.83	gold quality
smooth muscle tissue	UBERON:0001135	92.68	gold quality
pons	UBERON:0000988	92.58	gold quality
skeletal muscle tissue	UBERON:0001134	92.57	gold quality
tibialis anterior	UBERON:0001385	92.48	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.26	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-6	yes	40.63
E-ANND-3	yes	8.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

171 targeting HBS1L, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642

Literature-anchored findings (GeneRIF, showing 25)

• HBS1L-related genetic variants play a key role in control of fetal hemoglobin levels. (PMID:17592125)
• The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts. (PMID:17712044)
• Association of SNP in exon 1 of HBS1L with hemoglobin F level in beta0-thalassemia/hemoglobin E. (PMID:18839276)
• crystal structures of the MLLE domain from PABPC1 in complex with the two PAM2 regions of eRF3 (PMID:20418951)
• SNPs in BCL11A and the HBS1L-MYB region did not show statistically significant correlations with HbFlevels.This suggests that the BCL11A and HBS1L-MYB loci have a minor effect on HbF level compared to the XmnI QTL in beta-thalassemia intermedia patients. (PMID:20472475)
• A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. (PMID:21385855)
• Pelota/Hbs1 induced dissociation of elongation complexes from ribosomes and release of peptidyl-tRNA, but only in the presence of ABCE1. (PMID:21448132)
• Studies indicate that single nucleotide polymorphisms (SNPs) in regions of BCL11A and HBS1L-MYB intergenic polymorphism are the major modifiers of HbF in African Americans. (PMID:22936743)
• The non-stop decay mechanism exists in mammalian cells and involves Hbs1, Dom34, and the exosome-Ski complex. (PMID:23667253)
• Several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting interactions with MYB and MYB expression levels. This may explain the genetic association of HBS1L-MYB intergenic polymorphisms with erythroid traits and HbF levels. (PMID:24614105)
• Genetic variants of HBS1L is associated with sickle cell disease. (PMID:24667352)
• The study compares polymorphism at BCL11A to HBS1L-MYB loci and explains less of the variance in HbF in patients with sickle cell disease in Cameroon. (PMID:25488618)
• eRF3 neither interacts with the rRNA ribosephosphate backbone nor dissociates from the complex after GTP hydrolysis at translation termination. (PMID:26655225)
• we find that the interaction of UPF2 with UPF3b interferes with the assembly of the UPF2-eRF3 complex, and that UPF2 binds UPF3b more strongly than eRF3 (PMID:26740584)
• The HBS1L-MYB region contains two HbF QTLs, HMIP-2A and HMIP-2B (HBS1L-MYB intergenic polymorphisms A and B) HMIP-A is tagged by the SNP rs9399137, with the C" allele promoting HbF. Only 1 sickle cell patient had this allele. HMIP-B was tagged in these patients by rs4895441and represented Amerindian ethnic origin. (PMID:26849705)
• Knowledge of the interacting residues in the yeast complexes allowed identification of a splice variant of human HBS1-Like as a Ski7-like exosome-binding protein, revealing the evolutionary conservation of this cytoplasmic cofactor. (PMID:27345150)
• Induction of ribosome rescue factors PELO and HBS1L is required to support protein synthesis when ABCE1 levels fall in platelets, including for hemoglobin production during blood cell development. (PMID:27681415)
• Identification of HBS1LV3, a short splicing isoform of HBS1L, as a linker between the human cytoplasmic exosome and the SKI complex. (PMID:28204585)
• Studied association of BCL11A single nucleotide polymorphisms(snps) and HBS1L-MYB Intergenic snps with Hereditary Persistence of Fetal Hemoglobin (HPFH) in a cohort of sickle cell patients. (PMID:28332727)
• high-risk genotypes of six Hb F-associated SNPs, rs9376090, rs7776054, rs9399137, rs9389268, rs9402685 in the HBS1L-MYB intergenic region and rs189984760 in the BCL11A locus, showed association with high Hb F levels (PMID:28361591)
• genome-wide association analyses identified a new genome-wide significant locus on the HBS1L-MYB intergenic region for platelet-to-lymphocyte ratio (PMID:29066854)
• Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses. (PMID:30835870)
• Patients carrying Fetal Hemoglobin-boosting alleles of BCL11A and HMIP-2 ( (HBS1L-MYB) were associated with milder clinical phenotypes. Higher HbF concentration may underlie this effect. (PMID:32447424)
• Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences. (PMID:34099068)
• Induction of fetal hemoglobin: Lentiviral shRNA knockdown of HBS1L in beta0-thalassemia/HbE erythroid cells. (PMID:36888630)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hbs1l	ENSDARG00000036778
mus_musculus	Hbs1l	ENSMUSG00000019977
rattus_norvegicus	Hbs1l	ENSRNOG00000014531
drosophila_melanogaster	HBS1	FBGN0042712
caenorhabditis_elegans	hbs-1	WBGENE00010622

Paralogs (18): MTIF2 (ENSG00000085760), GTPBP1 (ENSG00000100226), EEF1A2 (ENSG00000101210), GSPT1 (ENSG00000103342), EFTUD2 (ENSG00000108883), EIF2S3 (ENSG00000130741), EEFSEC (ENSG00000132394), EFL1 (ENSG00000140598), GUF1 (ENSG00000151806), EEF1A1 (ENSG00000156508), EIF5B (ENSG00000158417), GFM2 (ENSG00000164347), EEF2 (ENSG00000167658), GFM1 (ENSG00000168827), GTPBP2 (ENSG00000172432), TUFM (ENSG00000178952), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

HBS1-like protein — Q9Y450 (reviewed: Q9Y450)

Alternative names: ERFS

All UniProt accessions (14): Q9Y450, B7Z524, D9YZV0, E9PHZ9, E9PJ90, E9PLR4, E9PMN1, E9PN23, E9PS53, G5E991, H0YD85, H0YDX7, H0YES5, J3QT46

UniProt curated annotations — full annotation on UniProt →

Function. GTPase component of the Pelota-HBS1L complex, a complex that recognizes stalled ribosomes and triggers the No-Go Decay (NGD) pathway. The Pelota-HBS1L complex recognizes ribosomes stalled at the 3’ end of an mRNA and engages stalled ribosomes by destabilizing mRNA in the mRNA channel. Following mRNA extraction from stalled ribosomes by the SKI complex, the Pelota-HBS1L complex promotes recruitment of ABCE1, which drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway.

Subunit / interactions. Component of the Pelota-HBS1L complex, also named Dom34-Hbs1 complex, composed of PELO and HBS1L. Interacts with the SKI complex. Associates with SKI complex; the interaction with SKIC2 is direct. Associates with the exosome complex; the interaction with EXOSC3 is direct.

Subcellular location. Cytoplasm Cytoplasm.

Tissue specificity. Detected in heart, brain, placenta, liver, muscle, kidney and pancreas.

Disease relevance. Defects in HBS1L have been found in one patient with a developmental disorder characterized by growth restriction, facial dysmorphism and developmental delay. Additional pleiotropic features include sparse hair and eyebrows, deep-set eyes with blue sclerae, bifid uvula with a submucous cleft palate, velopharyngeal insufficiency, C2-C3 vertebral fusion, scoliosis, vesicoureteral reflux with a bladder diverticulum and significant hypotonia. Deficiency is caused by the complete absence of isoform 1 and isoform 3, while isoform 2 is relatively unaffected in this patient.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y450-1	1, HBS1LV1	yes
Q9Y450-2	2, HBS1LV3
Q9Y450-4	3

RefSeq proteins (4): NP_001138630, NP_001138679, NP_001350615, NP_006611* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR004161	EFTu-like_2	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR009001	Transl_elong_EF1A/Init_IF2_C	Homologous_superfamily
IPR015033	HBS1-like_N	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037189	HBS1-like_N_sf	Homologous_superfamily
IPR050100	TRAFAC_GTPase_members	Family
IPR054696	GTP-eEF1A_C	Domain

Pfam: PF00009, PF03144, PF08938, PF22594

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (27 total): modified residue 9, region of interest 7, binding site 3, splice variant 2, sequence variant 2, chain 1, domain 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
11MR	ELECTRON MICROSCOPY	2.6
10AY	ELECTRON MICROSCOPY	2.9
9G8M	ELECTRON MICROSCOPY	3.3
9G8O	ELECTRON MICROSCOPY	3.4
9G8R	ELECTRON MICROSCOPY	3.4
5LZZ	ELECTRON MICROSCOPY	3.47
5LZW	ELECTRON MICROSCOPY	3.53
5LZX	ELECTRON MICROSCOPY	3.67
9G8N	ELECTRON MICROSCOPY	3.7
5LZY	ELECTRON MICROSCOPY	3.99
9G8P	ELECTRON MICROSCOPY	7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y450-F1	74.23	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 406–409; 445–447; 267–274

Post-translational modifications (9): 49, 67, 117, 127, 152, 154, 231, 622, 246

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-9954714	PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA

MSigDB gene sets: 205 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DARWICHE_SKIN_TUMOR_PROMOTER_UP, GOBP_TRANSLATIONAL_INITIATION, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_TRANSLATION, GOBP_POSITIVE_REGULATION_OF_TRANSLATIONAL_INITIATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, MARTINEZ_RB1_TARGETS_UP, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, TGACATY_UNKNOWN, GOBP_TRANSLATIONAL_ELONGATION

GO Biological Process (8): translation (GO:0006412), regulation of translation (GO:0006417), signal transduction (GO:0007165), ribosome disassembly (GO:0032790), nuclear-transcribed mRNA catabolic process, no-go decay (GO:0070966), rescue of stalled cytosolic ribosome (GO:0072344), translational elongation (GO:0006414), negative regulation of gene expression (GO:0010629)

GO Molecular Function (6): translation elongation factor activity (GO:0003746), GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): cytosol (GO:0005829), membrane (GO:0016020), cytosolic ribosome (GO:0022626), extracellular exosome (GO:0070062), Dom34-Hbs1 complex (GO:1990533), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
translational elongation	2
macromolecule biosynthetic process	2
translation	2
peptidyltransferase activity	1
translational initiation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
organelle disassembly	1
nuclear-transcribed mRNA catabolic process	1
cytoplasmic translational elongation	1
ribosome disassembly	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
translation factor activity	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
cytosol	1
ribosome	1
extracellular vesicle	1
protein-containing complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2073 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HBS1L	UPF1	Q92900	972
HBS1L	HBG1	P02096	951
HBS1L	PELO	Q9BRX2	939
HBS1L	A0A0J9YYA3	A0A0J9YYA3	931
HBS1L	ABCE1	P61221	928
HBS1L	MIPEP	Q99797	919
HBS1L	ETF1	P46055	912
HBS1L	UPF2	Q9HAU5	906
HBS1L	BCL11A	Q9H165	894
HBS1L	SMG1	Q96Q15	832
HBS1L	ZNF346	Q9UL40	822
HBS1L	UPF3A	Q9H1J1	820
HBS1L	LTN1	O94822	796
HBS1L	NEMF	O60524	767
HBS1L	TFAP4	Q01664	762

IntAct

106 interactions, top by confidence:

A	B	Type	Score
STK25	STRN	psi-mi:“MI:0914”(association)	0.900
EXOSC1	EXOSC10	psi-mi:“MI:0914”(association)	0.810
PELO	HBS1L	psi-mi:“MI:0915”(physical association)	0.780
EIF4E2	GIGYF1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DIS3L	EXOSC2	psi-mi:“MI:0914”(association)	0.690
FAM90A1	KPNA3	psi-mi:“MI:0914”(association)	0.670
HBS1L	DIS3L	psi-mi:“MI:0915”(physical association)	0.670
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
EXOSC4	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
EXOSC7	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
CACNG2	CCNT1	psi-mi:“MI:0914”(association)	0.530
RAB39B	CBL	psi-mi:“MI:0914”(association)	0.530
EXOSC8	PXN	psi-mi:“MI:0914”(association)	0.530
MSX2	ANKRD40	psi-mi:“MI:0914”(association)	0.530

BioGRID (181): PELO (Two-hybrid), HBS1L (Biochemical Activity), HBS1L (Affinity Capture-MS), HBS1L (Affinity Capture-MS), HBS1L (Affinity Capture-MS), HBS1L (Affinity Capture-MS), HBS1L (Affinity Capture-MS), HBS1L (Affinity Capture-MS), EIF2S3 (Co-fractionation), HBS1L (Co-fractionation), HBS1L (Co-fractionation), HBS1L (Affinity Capture-MS), HBS1L (Proximity Label-MS), HBS1L (Affinity Capture-MS), HBS1L (Affinity Capture-MS)

ESM2 similar proteins: A3KPE8, A4GNA8, A8E7G4, B4IB36, B4QL99, B6DMK2, O09053, O93530, O94443, P06623, P13233, P29375, P34529, P53331, P84634, Q14BI7, Q17902, Q1DKI1, Q1SGF1, Q28YQ7, Q2KHZ2, Q3EBC8, Q3MHU3, Q3UXZ9, Q5F3R2, Q5N870, Q5R6Y0, Q62240, Q682U6, Q69LX2, Q69ZS7, Q6AXM7, Q6ES10, Q6J5K9, Q7EYV7, Q7YTB0, Q7ZU90, Q80Y84, Q8L7M4, Q8LPU4

Diamond homologs: A0RUM4, A1RXW9, A2BN41, A2Q0Z0, A3DMQ1, A5DPE3, A8ABM5, O13354, O24534, O42820, O49169, O64937, O74718, O93729, P02993, P05453, P06805, P08736, P0CN30, P0CN31, P0CT31, P0CT32, P0CT53, P0CT54, P0CT55, P0CY35, P0DH99, P10126, P13549, P14864, P14865, P14963, P15170, P17507, P17508, P17786, P23637, P25166, P25698, P28295

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA decay by 3’ to 5’ exoribonuclease	7	61.7×	2e-09
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	7	54.8×	2e-09
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	7	54.8×	2e-09
KSRP (KHSRP) binds and destabilizes mRNA	7	54.8×	2e-09
Nuclear RNA decay	10	38.1×	3e-11
ATF4 activates genes in response to endoplasmic reticulum stress	7	35.2×	6e-08
Major pathway of rRNA processing in the nucleolus and cytosol	12	9.2×	4e-07
Metabolism of RNA	9	4.6×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
RNA catabolic process	11	44.7×	4e-13
rRNA catabolic process	5	44.2×	5e-06
RNA processing	11	21.5×	8e-10
rRNA processing	11	13.9×	4e-08
ribosomal small subunit biogenesis	5	10.2×	6e-03
negative regulation of translation	5	8.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

90 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2787 predictions. Top by Δscore:

Variant	Effect	Δscore
6:134965197:T:TA	donor_gain	1.0000
6:134966471:AACC:A	acceptor_loss	1.0000
6:134966473:CCTA:C	acceptor_loss	1.0000
6:134966474:C:CA	acceptor_loss	1.0000
6:134966475:T:A	acceptor_loss	1.0000
6:134969236:A:AC	donor_gain	1.0000
6:134969237:C:CC	donor_gain	1.0000
6:134969240:AGG:A	donor_gain	1.0000
6:134978677:A:AC	donor_gain	1.0000
6:134978678:C:CC	donor_gain	1.0000
6:134978788:C:CC	acceptor_gain	1.0000
6:134979173:CTCA:C	donor_gain	1.0000
6:134979176:A:AC	donor_gain	1.0000
6:134979177:C:CC	donor_gain	1.0000
6:134982563:C:CC	acceptor_gain	1.0000
6:134982563:C:T	acceptor_loss	1.0000
6:134982564:T:C	acceptor_loss	1.0000
6:134985336:CTTA:C	donor_loss	1.0000
6:134985337:TTAC:T	donor_loss	1.0000
6:134985338:TAC:T	donor_loss	1.0000
6:134985339:A:AC	donor_gain	1.0000
6:134985339:A:AG	donor_loss	1.0000
6:134985339:AC:A	donor_gain	1.0000
6:134985340:C:CT	donor_gain	1.0000
6:134985340:CC:C	donor_gain	1.0000
6:134985340:CCT:C	donor_gain	1.0000
6:134985405:GGAAT:G	acceptor_gain	1.0000
6:134985406:GAAT:G	acceptor_gain	1.0000
6:134985408:AT:A	acceptor_gain	1.0000
6:134985408:ATC:A	acceptor_loss	1.0000

AlphaMissense

4484 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:134966342:C:T	G677D	1.000
6:134966345:G:T	A676D	1.000
6:134966348:G:T	A675D	1.000
6:134987654:T:A	K407N	1.000
6:134987654:T:G	K407N	1.000
6:134987655:T:A	K407I	1.000
6:134987656:T:C	K407E	1.000
6:134987685:C:T	G397E	1.000
6:134987694:C:G	R394P	1.000
6:134987697:A:T	V393D	1.000
6:134987700:A:G	L392S	1.000
6:134987720:T:A	Q385H	1.000
6:134987720:T:G	Q385H	1.000
6:134987739:C:T	G379E	1.000
6:134987740:C:G	G379R	1.000
6:134987740:C:T	G379R	1.000
6:134987747:A:C	F376L	1.000
6:134987747:A:T	F376L	1.000
6:134987749:A:G	F376L	1.000
6:134987791:C:G	A362P	1.000
6:134993786:A:T	I352N	1.000
6:134993788:G:C	F351L	1.000
6:134993788:G:T	F351L	1.000
6:134993789:A:G	F351S	1.000
6:134993790:A:G	F351L	1.000
6:134993797:A:C	H348Q	1.000
6:134993797:A:T	H348Q	1.000
6:134993799:G:C	H348D	1.000
6:134993801:C:T	G347D	1.000
6:134993802:C:G	G347R	1.000

dbSNP variants (sampled 300 via entrez): RS1000039300 (6:134991942 C>A,G,T), RS1000061290 (6:135039805 G>C), RS1000119348 (6:134978379 T>C,G), RS1000177128 (6:135037990 T>C,G), RS1000202301 (6:134994412 T>C), RS1000280096 (6:135012591 T>C), RS1000287867 (6:134968741 T>C,G), RS1000308847 (6:134998916 A>G), RS1000331898 (6:135046210 C>T), RS1000345724 (6:135001919 TA>T,TAA), RS1000376960 (6:135001493 CTCTG>C), RS1000387012 (6:135044714 T>C), RS1000417327 (6:135052267 A>T), RS1000472007 (6:135005680 C>A,T), RS1000535015 (6:134987320 T>C)

Disease associations

OMIM: gene MIM:612450 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
retinal disorder	Moderate	Autosomal recessive

Mondo (1): retinal disorder (MONDO:0005283)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

173 associations (top):

Study	Trait	p-value
GCST000498_8	Hematological parameters	7.000000e-42
GCST000500_1	Other erythrocyte phenotypes	1.000000e-47
GCST000500_2	Other erythrocyte phenotypes	7.000000e-14
GCST000502_7	Hematocrit	3.000000e-15
GCST000503_12	Mean corpuscular volume	7.000000e-86
GCST000504_8	Mean corpuscular hemoglobin	7.000000e-69
GCST000510_1	Platelet count	1.000000e-09
GCST000532_2	Beta thalassemia/hemoglobin E disease	2.000000e-11
GCST000580_2	Platelet count	3.000000e-14
GCST000582_2	Mean corpuscular hemoglobin concentration	6.000000e-12
GCST000583_5	Hematological and biochemical traits	1.000000e-10
GCST000585_1	Mean corpuscular volume	3.000000e-56
GCST000587_6	Mean corpuscular hemoglobin	3.000000e-66
GCST000588_3	Red blood cell count	7.000000e-48
GCST000589_5	White blood cell count	2.000000e-09
GCST000814_12	Red blood cell traits	3.000000e-15
GCST000814_5	Red blood cell traits	3.000000e-08
GCST000814_6	Red blood cell traits	6.000000e-09
GCST000814_7	Red blood cell traits	1.000000e-08
GCST000814_8	Red blood cell traits	1.000000e-14
GCST000814_9	Red blood cell traits	1.000000e-15
GCST001134_9	White blood cell types	1.000000e-10
GCST001337_20	Platelet count	5.000000e-47
GCST001710_1	HbA2 levels	5.000000e-09
GCST001765_2	Red blood cell traits	3.000000e-19
GCST001779_3	Hematology traits	3.000000e-06
GCST001780_6	Mean corpuscular hemoglobin	4.000000e-13
GCST001780_9	Mean corpuscular hemoglobin	4.000000e-15
GCST001781_3	Mean corpuscular volume	2.000000e-09
GCST001781_6	Mean corpuscular volume	1.000000e-11

EFO canonical traits (31, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004348	hematocrit
EFO:0004527	mean corpuscular hemoglobin
EFO:0004309	platelet count
EFO:0004509	hemoglobin measurement
EFO:0004842	eosinophil count
EFO:0005845	hemoglobin A2 measurement
EFO:0004574	total cholesterol measurement
EFO:0004541	HbA1c measurement
EFO:0004576	fetal hemoglobin measurement
EFO:0004251	myeloproliferative disorder
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007985	platelet crit
EFO:0007986	reticulocyte count
EFO:0004833	neutrophil count
EFO:0007987	granulocyte count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0009188	Red cell distribution width
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005091	monocyte count
EFO:0004736	aspartate aminotransferase measurement
EFO:0010417	triacylglycerol 52:5 measurement
EFO:0010426	triacylglycerol 54:8 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0006333	transferrin saturation measurement
EFO:0006334	total iron binding capacity
EFO:0004587	lymphocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D012164	Retinal Diseases	C11.768

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067248 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.37	Kd	42.69	nM	CHEMBL5653589
7.34	ED50	46.05	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148489: Binding affinity to human HBS1L incubated for 45 mins by Kinobead based pull down assay	kd	0.0427	uM

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
ochratoxin A	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment	1
Caffeine	decreases phosphorylation	1
Curcumin	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Progesterone	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651531	Binding	Binding affinity to human HBS1L incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

27 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT04311112	PHASE2/PHASE3	WITHDRAWN	Safety and Efficacy of Zuretinol Acetate in Subjects With Inherited Retinal Disease
NCT04008121	EARLY_PHASE1	RECRUITING	Feasibility and Safety of MB-102 in Ocular Angiography as Compared to Fluorescein Sodium
NCT00259701	Not specified	COMPLETED	Microvascular Reactivity.
NCT00331370	Not specified	UNKNOWN	Hypertension Related Damage to the Microcirculation in South Asian: Emergence, Predictive Power and Reversibility
NCT00618644	Not specified	WITHDRAWN	Ranibizumab for Neovascularization in Sickle Cell Retinopathy
NCT00735657	Not specified	COMPLETED	Anesthesia for Pars Plana Vitrectomy (PPV) With Insulin Needle
NCT00828425	Not specified	COMPLETED	Management of Diabetes Mellitus Patients With Retinopathy
NCT00969956	Not specified	TERMINATED	Time To Complications Occurs in Diabetes
NCT01412905	Not specified	COMPLETED	Telemedicine Retinal Screening Utilizing a Mobile Medical Unit
NCT01546766	Not specified	COMPLETED	Rapid, Non-invasive, Regional Functional Imaging of the Retina. (Diabetic Retinopathy Diagnosis Device)
NCT01552993	Not specified	TERMINATED	Registration and Treatment of Pain During Eye Examination of Prematurity
NCT01815567	Not specified	COMPLETED	DETECT and Retinal Outcomes in Hypertension
NCT02321904	Not specified	COMPLETED	Corneal Confocal Microscopy to Detect Diabetic Neuropathy in Children
NCT02466607	Not specified	COMPLETED	Study of Stimulus Parameters in Flicker Electroretinogram (ERG)
NCT02558478	Not specified	UNKNOWN	Identification of New Genes Implicated in Rare Neurosensory Diseases by Whole Exome Sequencing
NCT02702973	Not specified	UNKNOWN	Characteristic Analysis of Retinopathy Associated With High Doses of Interferon α-2b Therapy
NCT03011541	Not specified	RECRUITING	Stem Cell Ophthalmology Treatment Study II
NCT03542734	Not specified	RECRUITING	Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly
NCT03901898	Not specified	COMPLETED	Feasibility of an Intervention to Increase Diabetic Retinopathy Screening Attendance
NCT04819893	Not specified	RECRUITING	Study of the Involvement of Fatty Acids in Retinopathy of Prematurity: Relationship Between Retinopathy of Prematurity and the Rate of Expression of Transplacental Fatty Acid Receptors.
NCT05921981	Not specified	COMPLETED	Multisensory Stimulation Versus White Noise
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06355219	Not specified	COMPLETED	Macrovascular and Microvascular Morbidity and Mortality After Metabolic Surgery Versus Medicines
NCT06837181	Not specified	RECRUITING	Studying the Presence of CFRD Complications With Thoughtful Recruitment (SPeCTRuM)