HELLS

Summary

HELLS (helicase, lymphoid specific, HGNC:4861) is a protein-coding gene on chromosome 10q23.33, encoding Lymphoid-specific helicase (Q9NRZ9). ATP-dependent chromatin remodeler that regulates chromatin accessibility, DNA methylation, and histone modifications.

This gene encodes a lymphoid-specific helicase. Other helicases function in processes involving DNA strand separation, including replication, repair, recombination, and transcription. This protein is thought to be involved with cellular proliferation and may play a role in leukemogenesis. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 3070 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency-centromeric instability-facial anomalies syndrome 4 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 481 total — 16 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• MANE Select transcript: NM_018063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4861
Approved symbol	HELLS
Name	helicase, lymphoid specific
Location	10q23.33
Locus type	gene with protein product
Status	Approved
Aliases	PASG, SMARCA6, LSH, Nbla10143, SALNR
Ensembl gene	ENSG00000119969
Ensembl biotype	protein_coding
OMIM	603946
Entrez	3070

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 14 protein_coding, 7 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000348459, ENST00000371327, ENST00000371332, ENST00000394036, ENST00000394045, ENST00000419900, ENST00000462057, ENST00000464030, ENST00000466552, ENST00000475263, ENST00000630929, ENST00000698650, ENST00000698651, ENST00000698672, ENST00000698673, ENST00000698674, ENST00000698675, ENST00000698676, ENST00000698799, ENST00000698800, ENST00000698830, ENST00000939522, ENST00000939523, ENST00000939524, ENST00000939525, ENST00000939526, ENST00000939527, ENST00000939528

RefSeq mRNA: 10 — MANE Select: NM_018063 NM_001289067, NM_001289068, NM_001289069, NM_001289070, NM_001289071, NM_001289072, NM_001289073, NM_001289074, NM_001289075, NM_018063

CCDS: CCDS73162, CCDS73163, CCDS7434, CCDS91306, CCDS91307, CCDS91308

Canonical transcript exons

ENST00000348459 — 22 exons

Exon	Start	End
ENSE00001608347	94554126	94554248
ENSE00001892305	94601528	94602099
ENSE00003498122	94558139	94558195
ENSE00003678073	94562812	94562876
ENSE00003711587	94582963	94583059
ENSE00003720104	94573960	94574187
ENSE00003720177	94574554	94574736
ENSE00003721299	94592395	94592514
ENSE00003721919	94594695	94594854
ENSE00003726607	94592229	94592312
ENSE00003730608	94571388	94571429
ENSE00003732907	94581326	94581522
ENSE00003736853	94562691	94562727
ENSE00003738428	94588229	94588390
ENSE00003741233	94597035	94597111
ENSE00003741828	94590638	94590776
ENSE00003742425	94593499	94593615
ENSE00003746805	94596860	94596956
ENSE00003748813	94576662	94576805
ENSE00003748848	94590413	94590552
ENSE00003974392	94545788	94545952
ENSE00003974393	94546377	94546498

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 94.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.8590 / max 824.6863, expressed in 1594 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106323	21.8896	1536
106322	2.2342	861
106324	0.7351	346

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.22	gold quality
ventricular zone	UBERON:0003053	92.84	gold quality
oocyte	CL:0000023	90.89	gold quality
secondary oocyte	CL:0000655	89.96	gold quality
ganglionic eminence	UBERON:0004023	89.80	gold quality
adrenal tissue	UBERON:0018303	87.44	gold quality
embryo	UBERON:0000922	84.88	gold quality
colonic epithelium	UBERON:0000397	84.50	gold quality
thymus	UBERON:0002370	82.08	gold quality
testis	UBERON:0000473	81.73	gold quality
right testis	UBERON:0004534	81.70	gold quality
mucosa of transverse colon	UBERON:0004991	80.56	gold quality
tibia	UBERON:0000979	80.40	gold quality
trabecular bone tissue	UBERON:0002483	80.18	gold quality
tonsil	UBERON:0002372	80.07	gold quality
left testis	UBERON:0004533	80.05	gold quality
oral cavity	UBERON:0000167	79.93	gold quality
epithelium of nasopharynx	UBERON:0001951	79.88	gold quality
buccal mucosa cell	CL:0002336	79.33	gold quality
endometrium	UBERON:0001295	78.99	gold quality
calcaneal tendon	UBERON:0003701	78.72	gold quality
bone marrow	UBERON:0002371	78.57	gold quality
lymph node	UBERON:0000029	77.86	gold quality
stromal cell of endometrium	CL:0002255	77.65	gold quality
bone marrow cell	CL:0002092	77.28	gold quality
esophagus mucosa	UBERON:0002469	76.57	gold quality
mucosa of sigmoid colon	UBERON:0004993	76.31	gold quality
rectum	UBERON:0001052	76.09	gold quality
sural nerve	UBERON:0015488	75.34	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-6075	yes	1975.91
E-CURD-6	yes	1361.85
E-MTAB-7051	yes	1024.87
E-GEOD-93593	yes	599.13
E-MTAB-10662	yes	413.69
E-GEOD-76312	yes	359.80
E-MTAB-11121	yes	301.51
E-HCAD-23	yes	297.65
E-MTAB-10485	yes	265.97
E-MTAB-10290	yes	218.54
E-CURD-114	yes	206.07
E-MTAB-8530	yes	174.75
E-MTAB-6678	yes	10.23
E-ANND-3	yes	7.47
E-MTAB-6819	no	867.37

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, FOXM1

miRNA regulators (miRDB)

24 targeting HELLS, 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-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-4795-5P	99.11	66.90	876
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-4264	96.35	64.76	1480

Literature-anchored findings (GeneRIF, showing 34)

• LSH serves as a recruiting factor for DNA methyltransferases and histone deacetylases to establish transcriptionally repressive chromatin which is perhaps further stabilized by DNA methylation at targeted loci (PMID:17967891)
• These results suggest differences in cellular consequences of hypomethylation mediated by PASG during development compared to that in somatic cells. (PMID:18948754)
• Lsh overexpression delays cell senescence by silencing p16(INK4a) in human fibroblasts. (PMID:19561196)
• Data provide strong evidence that CEP55 and HELLS may be used in conjunction with FOXM1 as a biomarker set for early cancer detection and indicators of malignant conversion and progression. (PMID:20400365)
• E2F1 plays a crucial role in transcriptional control of the human Lsh gene and the decrease of Lsh expression in senescent cells is related to the repression of E2F1 (PMID:21453717)
• just as E2F3, HELLS is overexpressed in human tumours including prostate cancer, indicating that either factor may contribute to the malignant progression of tumours (PMID:22157815)
• Upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK. (PMID:25338120)
• Mutations of HELLS gene is associated with stomach and colorectal cancers. (PMID:25351940)
• Mutations in HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome type 4. (PMID:26216346)
• LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH). (PMID:27302170)
• High mRNA levels of HELLS is independent predictor of poor outcome in Renal Cell Carcinoma patients. (PMID:28069330)
• This study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis (PMID:28900510)
• LSH is likely one of the mechanisms of genome instability underlying 5-hydroxymethylcytosine loss in cancer. (PMID:29109788)
• HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex; immunodeficiency-centromeric instability-facial anomalies syndrome has a defective HELLS and CDCA7 bipartite nucleosome remodeling complex (PMID:29339483)
• Here, we performed a comparative analysis of perturbed DNA methylation landscapes in a cohort of ICF patients using an array-based assay to (i) evaluate the similarities and differences in methylation landscapes depending on patient genotypes as an index of a functional link between the four ICF factors, (ii) identify genomic regions that rely on DNMT3B, ZBTB24, CDCA7 or HELLS for their methylation status (PMID:29659838)
• in contrast to Immunodeficiency, Centromeric instability and Facial anomalies syndrome type 1 (ICF1), the subtelomeric methylation patterns in cells of ICF2-4 patients do not differ significantly from those in normal cells, and ICF2-4 cells exhibit a normal telomeric phenotype. Also knocking down the expression of ZBTB24, CDCA7 and HELLS in normal human fibroblasts does not affect subtelomeric methylation. (PMID:30010917)
• the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome cells, including centromeric instability, abnormal chromosome segregation, and apoptosis. (PMID:30307408)
• By altering the nucleosome occupancy at the nucleosome-free region and enhancer, HELLS epigenetically suppresses multiple tumor suppressor genes to promote hepatocellular carcinoma progression. (PMID:30516846)
• Glioblastoma stem cells (GSCs) preferentially expressed HELLS compared with their differentiated tumor progeny and normal brain cells. Elevated HELLS expression associated with poor prognosis of glioma patients. HELLS interacts with E2F3 and MYC to regulate gene expression critical to GSC proliferation. HELLS expression strongly correlated with targets of E2F3 and MYC transcriptional activity in glioblastoma patients. (PMID:30779712)
• Study shows that report that LSH was overexpressed in tumor tissues of hepatocellular carcinoma (HCC), and overexpression of LSH was associated with poor prognosis. LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis. (PMID:31066149)
• GINS4 facilitates lung cancer progression by promoting key characteristics of tumor potential, and LSH epigenetically interacts with and stabilizes GINS4 transcripts. (PMID:31253190)
• LSH enables cells to maintain a low level of p53 by targeting MDM2; however, upon genotoxic stress such as DNA damage, LSH, p53, and PKM2 might be rapidly induced to form a complex, thereby enhancing LSH targeting of p53 and antagonizing the ubiquitination of p53. (PMID:31594538)
• This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts (PMID:31802118)
• Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination. (PMID:32727902)
• The cross-talk between methylation and phosphorylation in lymphoid-specific helicase drives cancer stem-like properties. (PMID:32994405)
• CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats. (PMID:33082427)
• A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association. (PMID:33170271)
• Suppression of HELLS by miR-451a represses mTOR pathway to hinder aggressiveness of SCLC. (PMID:33460027)
• The DNA-helicase HELLS drives ALK(-) ALCL proliferation by the transcriptional control of a cytokinesis-related program. (PMID:33504766)
• Lymphoid-specific helicase in epigenetics, DNA repair and cancer. (PMID:34493821)
• Hsa_circ_0072008 regulates cell proliferation, migration, and invasion in cervical squamous cell carcinoma via miR-1305/helicase, lymphoid specific (HELLS) axis. (PMID:35311456)
• Diagnostic, Prognostic, and Immunological Roles of HELLS in Pan-Cancer: A Bioinformatics Analysis. (PMID:35774795)
• The Chromatin Remodeler HELLS: A New Regulator in DNA Repair, Genome Maintenance, and Cancer. (PMID:36012581)
• Lost in HELLS: Disentangling the mystery of SALNR existence in senescence cellular models. (PMID:37252915)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hells	ENSDARG00000057738
mus_musculus	Hells	ENSMUSG00000025001
rattus_norvegicus	Hells	ENSRNOG00000047692

Paralogs (30): HLTF (ENSG00000071794), SMARCA2 (ENSG00000080503), SRCAP (ENSG00000080603), ATRX (ENSG00000085224), RAD54L (ENSG00000085999), BTAF1 (ENSG00000095564), CHD8 (ENSG00000100888), SMARCA1 (ENSG00000102038), CHD4 (ENSG00000111642), CHD5 (ENSG00000116254), TTF2 (ENSG00000116830), ZRANB3 (ENSG00000121988), CHD6 (ENSG00000124177), SMARCA4 (ENSG00000127616), INO80 (ENSG00000128908), CHD1L (ENSG00000131778), SMARCAL1 (ENSG00000138375), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), SMARCAD1 (ENSG00000163104), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

Lymphoid-specific helicase — Q9NRZ9 (reviewed: Q9NRZ9)

Alternative names: Proliferation-associated SNF2-like protein, SWI/SNF2-related matrix-associated actin-dependent regulator of chromatin subfamily A member 6

All UniProt accessions (7): A0A087WSW7, A0A0B4J1V9, A0A8V8TMK7, B1ALG6, Q9NRZ9, F6RPV8, Q76H82

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent chromatin remodeler that regulates chromatin accessibility, DNA methylation, and histone modifications. It facilitates de novo DNA methylation at repetitive sequences and promotes transcriptional silencing via recruitment of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), contributing to heterochromatin formation and repression of transposable elements. Also involved in DNA repair by recruiting DNA damage response mediators to double-strand breaks in heterochromatin, promoting homologous recombination via RBBP8/CtIP-dependent end resection. During meiosis, it is recruited by PRDM9 to recombination hotspots, aiding chromatin opening. Through these diverse roles, is crucial for processes such as development, differentiation, and genomic stability. Involved in regulation of the expansion or survival of lymphoid cells.

Subunit / interactions. Interacts with RBBP8/CtIP; the interaction leads to recruitment of RBBP8/CtIP to sites of DNA breaks. Interacts with PRDM9; the interaction recruits HELLS to meiotic recombination hot spots. Interacts with CDCA7; the interaction brings HELLS to chromatin and recruits DNA methyltransferases to heterochromatin regions.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Highly expressed in proliferative tissues such as adult thymus and testis, and expressed at lower levels in uterus, small intestine, colon, and peripheral blood mononuclear cells. Also expressed in neoplastic cell lines including those derived from myeloid and lymphoid leukemias.

Disease relevance. Immunodeficiency-centromeric instability-facial anomalies syndrome 4 (ICF4) [MIM:616911] A rare disorder characterized by a variable immunodeficiency resulting in recurrent infections, facial anomalies, and branching of chromosomes 1, 9, and 16. Other variable symptoms include growth retardation, failure to thrive, and psychomotor retardation. Laboratory studies show limited hypomethylation of DNA in a small fraction of the genome in some, but not all, patients. The disease may be caused by variants affecting the gene represented in this entry.

Induction. By concanavalin-A in peripheral blood leukocytes.

Similarity. Belongs to the SNF2/RAD54 helicase family.

Isoforms (9)

UniProt ID	Names	Canonical?
Q9NRZ9-1	1	yes
Q9NRZ9-2	2
Q9NRZ9-3	3
Q9NRZ9-4	4
Q9NRZ9-5	5
Q9NRZ9-6	6
Q9NRZ9-7	7
Q9NRZ9-8	8
Q9NRZ9-9	9

RefSeq proteins (10): NP_001275996, NP_001275997, NP_001275998, NP_001275999, NP_001276000, NP_001276001, NP_001276002, NP_001276003, NP_001276004, NP_060533* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR044753	HELLS_N	Domain
IPR049730	SNF2/RAD54-like_C	Domain

Pfam: PF00176, PF00271

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (31 total): splice variant 11, sequence conflict 4, modified residue 3, sequence variant 3, domain 2, compositionally biased region 2, chain 1, mutagenesis site 1, region of interest 1, coiled-coil region 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9Z05	ELECTRON MICROSCOPY	2.86
9Z04	ELECTRON MICROSCOPY	2.99
9Z06	ELECTRON MICROSCOPY	3.39
8SKZ	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRZ9-F1	68.76	0.20

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 (1): 248–255

Post-translational modifications (3): 503, 515, 115

Mutagenesis-validated functional residues (1):

Position	Phenotype
254	disrupts double-strand break (dsb) repair. no effect on interaction to rbbp8 or binding to chromatin.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9839394	TGFBR3 expression

MSigDB gene sets: 344 (showing top): HORIUCHI_WTAP_TARGETS_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_RESPONSE_TO_PEPTIDE, PAL_PRMT5_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PATIL_LIVER_CANCER, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_DNA_METHYLATION_DEPENDENT_CONSTITUTIVE_HETEROCHROMATIN_FORMATION

GO Biological Process (16): double-strand break repair via homologous recombination (GO:0000724), urogenital system development (GO:0001655), kidney development (GO:0001822), double-strand break repair (GO:0006302), DNA methylation-dependent constitutive heterochromatin formation (GO:0006346), apoptotic process (GO:0006915), pericentric heterochromatin formation (GO:0031508), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), lymphocyte proliferation (GO:0046651), cell division (GO:0051301), chromosomal DNA methylation maintenance following DNA replication (GO:0141119), cellular response to leukemia inhibitory factor (GO:1990830), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243), chromatin remodeling (GO:0006338), heterochromatin formation (GO:0031507), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (8): chromatin binding (GO:0003682), helicase activity (GO:0004386), ATP binding (GO:0005524), hydrolase activity (GO:0016787), chromatin-protein adaptor activity (GO:0140463), ATP-dependent chromatin remodeler activity (GO:0140658), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (4): chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), pericentric heterochromatin (GO:0005721), site of double-strand break (GO:0035861)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromatin organization	3
renal system development	2
constitutive heterochromatin formation	2
negative regulation of gene expression, epigenetic	2
binding	2
recombinational repair	1
double-strand break repair	1
system development	1
animal organ development	1
DNA repair	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
mononuclear cell proliferation	1
lymphocyte activation	1
cellular process	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
intrinsic apoptotic signaling pathway	1
negative regulation of intracellular signal transduction	1
negative regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
cellular component assembly	1
heterochromatin boundary formation	1
heterochromatin organization	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
ATP-dependent activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
chromatin binding	1
protein-macromolecule adaptor activity	1
DNA binding	1
chromatin remodeling	1
ATP-dependent activity, acting on DNA	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

3806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HELLS	DNMT3B	Q9UBC3	912
HELLS	WDR76	Q9H967	869
HELLS	DNMT3A	Q9Y6K1	788
HELLS	CDCA7	Q9BWT1	783
HELLS	ZBTB24	O43167	711
HELLS	HOXA7	P31268	611
HELLS	R4GMX3	R4GMX3	571
HELLS	BMI1	P35226	570
HELLS	EHMT2	Q96KQ7	566
HELLS	HDAC1	Q13547	538
HELLS	RAD51	Q06609	533
HELLS	WRN	Q14191	512
HELLS	DNMT1	P26358	502
HELLS	SUZ12	Q15022	493
HELLS	UHRF1	Q96T88	491

IntAct

90 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC39A9	B4GALT5	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
HELLS	E2F3	psi-mi:“MI:0915”(physical association)	0.500
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
FOXA3	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXE1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXG1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXQ1	DDX39A	psi-mi:“MI:0914”(association)	0.350
TEAD2	DDX39A	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
P2RY6	RAVER1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
NUMA1	SHANK3	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
FURIN	ESYT2	psi-mi:“MI:0914”(association)	0.350
LDLRAD1	GXYLT2	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
SV2A	ILVBL	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MAGEA9	CIBAR1	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
TPX2	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350

BioGRID (269): HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Co-fractionation), WDR5 (Co-fractionation), HELLS (Proximity Label-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS), HELLS (Affinity Capture-MS)

ESM2 similar proteins: A0A0P0WGX7, A2BGR3, A3KFM7, A3KMI0, A4IHD2, A4PBL4, A6QQR4, B0R061, D3Z9Z9, D3ZA12, E1B7X9, F4I2H2, F4I9Q5, F4J9M5, F4JTF6, F4K128, F8VPZ5, G5EDG2, O14139, O18017, O42861, P0CQ66, P0CQ67, P32657, P32849, P32863, P40352, P87114, Q03468, Q04692, Q0D622, Q0PCS3, Q0WVW7, Q2NKX8, Q5FWR0, Q60EX7, Q6P158, Q6PGC1, Q7F2E4, Q7Z478

Diamond homologs: A0A0P0WGX7, A1C9W6, A1CZE5, A2BGR3, A2R9H9, A4H7G5, A4HVU6, A4IHD2, A4PBL4, A4R227, A5E0W5, A6QQR4, A6ZL17, A6ZU34, A7EQA8, A7TJI3, A7Z019, B3LN76, B4F769, B5VE38, B6EU02, C0H4W3, C7GQI8, E7F1C4, F4HW51, O13682, O14148, P0CO16, P0CO17, P0CO18, P0CO19, P32863, P34739, P36607, P38086, P41410, P43610, P46100, P51532, P53115

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	5
Uncertain significance	161
Likely benign	257
Benign	21

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1912517	NM_018063.5(HELLS):c.1519C>T (p.Arg507Ter)	Pathogenic
2091915	NM_018063.5(HELLS):c.1293_1296del (p.Arg432fs)	Pathogenic
225523	NM_018063.5(HELLS):c.2096A>G (p.Gln699Arg)	Pathogenic
225524	NM_018063.5(HELLS):c.370+2T>A	Pathogenic
225525	NM_018063.5(HELLS):c.2283_2286del (p.Ser762fs)	Pathogenic
225526	NM_018063.5(HELLS):c.610A>T (p.Lys204Ter)	Pathogenic
225527	NM_018063.5(HELLS):c.374_381dup (p.Lys128Ter)	Pathogenic
2796027	NM_018063.5(HELLS):c.1528C>T (p.Arg510Ter)	Pathogenic
2832125	NM_018063.5(HELLS):c.1816C>T (p.Arg606Ter)	Pathogenic
2833635	NM_018063.5(HELLS):c.1681C>T (p.Gln561Ter)	Pathogenic
2834655	NM_018063.5(HELLS):c.301G>T (p.Glu101Ter)	Pathogenic
3689335	NM_018063.5(HELLS):c.1390C>T (p.Arg464Ter)	Pathogenic
4279407	GRCh37/hg19 10q23.33(chr10:96305860-96415962)x1	Pathogenic
4725477	NM_018063.5(HELLS):c.715del (p.Glu239fs)	Pathogenic
4729589	NM_018063.5(HELLS):c.1158_1159delinsTT (p.Leu386_Gln387delinsPheTer)	Pathogenic
943584	NM_018063.5(HELLS):c.385del (p.Arg129fs)	Pathogenic
2006780	NM_018063.5(HELLS):c.1972-1G>A	Likely pathogenic
225528	NM_018063.5(HELLS):c.2394GTT[2] (p.Leu801del)	Likely pathogenic
3347608	NM_018063.5(HELLS):c.2007dup (p.Phe670fs)	Likely pathogenic
3649216	NM_018063.5(HELLS):c.31+2T>C	Likely pathogenic
3779727	NM_018063.5(HELLS):c.276+1G>A	Likely pathogenic

SpliceAI

3723 predictions. Top by Δscore:

Variant	Effect	Δscore
10:94546372:GTCA:G	acceptor_loss	1.0000
10:94546375:A:AG	acceptor_gain	1.0000
10:94546375:AGGCT:A	acceptor_loss	1.0000
10:94546376:G:A	acceptor_loss	1.0000
10:94546376:G:GG	acceptor_gain	1.0000
10:94554123:TAG:T	acceptor_loss	1.0000
10:94554124:A:AG	acceptor_gain	1.0000
10:94554125:G:C	acceptor_loss	1.0000
10:94554125:G:GG	acceptor_gain	1.0000
10:94554246:GAG:G	donor_gain	1.0000
10:94554248:GGT:G	donor_loss	1.0000
10:94554249:G:C	donor_loss	1.0000
10:94554249:G:GG	donor_gain	1.0000
10:94554250:T:G	donor_loss	1.0000
10:94558135:ACAG:A	acceptor_loss	1.0000
10:94558136:CAGGA:C	acceptor_loss	1.0000
10:94558137:A:AG	acceptor_gain	1.0000
10:94558137:A:T	acceptor_loss	1.0000
10:94558138:G:GG	acceptor_gain	1.0000
10:94574734:GAT:G	donor_gain	1.0000
10:94588221:A:AG	acceptor_gain	1.0000
10:94588222:A:G	acceptor_gain	1.0000
10:94588225:TTA:T	acceptor_loss	1.0000
10:94588226:TAGAT:T	acceptor_loss	1.0000
10:94588227:A:AC	acceptor_loss	1.0000
10:94588227:A:AG	acceptor_gain	1.0000
10:94588228:G:A	acceptor_loss	1.0000
10:94588228:G:GG	acceptor_gain	1.0000
10:94588228:GATT:G	acceptor_gain	1.0000
10:94588228:GATTT:G	acceptor_gain	1.0000

AlphaMissense

5575 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:94574179:T:A	W233R	1.000
10:94574179:T:C	W233R	1.000
10:94574183:T:C	L234P	1.000
10:94574579:G:A	G244D	1.000
10:94574590:G:C	D248H	1.000
10:94574599:G:A	G251R	1.000
10:94574599:G:C	G251R	1.000
10:94574605:G:C	G253R	1.000
10:94574606:G:A	G253D	1.000
10:94574606:G:T	G253V	1.000
10:94581373:G:C	K360N	1.000
10:94581373:G:T	K360N	1.000
10:94581429:T:C	L379P	1.000
10:94581471:T:C	L393P	1.000
10:94581473:T:A	W394R	1.000
10:94581473:T:C	W394R	1.000
10:94581483:T:C	L397P	1.000
10:94581506:T:C	F405L	1.000
10:94581508:T:A	F405L	1.000
10:94581508:T:G	F405L	1.000
10:94594735:G:C	R710T	1.000
10:94594736:A:C	R710S	1.000
10:94594736:A:T	R710S	1.000
10:94574170:G:C	G230R	0.999
10:94574181:G:C	W233C	0.999
10:94574181:G:T	W233C	0.999
10:94574558:T:C	L237P	0.999
10:94574578:G:C	G244R	0.999
10:94574582:T:A	I245N	0.999
10:94574585:T:C	L246S	0.999

dbSNP variants (sampled 300 via entrez): RS1000042989 (10:94604350 C>T), RS1000057289 (10:94614363 GAC>G), RS1000073281 (10:94581162 G>A,C), RS1000075689 (10:94604678 A>G), RS1000126925 (10:94561769 A>C), RS1000165321 (10:94578139 C>T), RS1000212542 (10:94572664 C>A,T), RS1000259152 (10:94577988 G>A), RS1000261452 (10:94550288 G>A), RS1000265322 (10:94584370 G>A), RS1000339181 (10:94584112 A>G,T), RS1000377220 (10:94584891 A>C,G), RS1000464835 (10:94598343 G>A), RS1000559600 (10:94560263 C>T), RS1000570488 (10:94577426 T>C)

Disease associations

OMIM: gene MIM:603946 | disease phenotypes: MIM:616911

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency-centromeric instability-facial anomalies syndrome 4	Strong	Autosomal recessive
immunodeficiency-centromeric instability-facial anomalies syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency-centromeric instability-facial anomalies syndrome 4	Moderate	AR

Mondo (2): immunodeficiency-centromeric instability-facial anomalies syndrome 4 (MONDO:0014829), immunodeficiency-centromeric instability-facial anomalies syndrome (MONDO:0000133)

Orphanet (1): ICF syndrome (Orphanet:2268)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001334	Communicating hydrocephalus
HP:0001537	Umbilical hernia
HP:0001874	Abnormality of neutrophils
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0002024	Malabsorption
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002846	Abnormal B cell morphology
HP:0003220	Abnormality of chromosome stability
HP:0003577	Congenital onset
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004322	Short stature
HP:0004432	Agammaglobulinemia
HP:0005280	Depressed nasal bridge
HP:0005374	Cellular immunodeficiency
HP:0010808	Protruding tongue
HP:0012368	Flat face

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006206_3	Thiopurine-induced alopecia in inflammatory bowel disease	1.000000e-06
GCST007684_2	Plasma clozapine-norclozapine ratio in treatment-resistant schizophrenia	5.000000e-14
GCST008374_1	Warfarin maintenance dose (adjusted for clinical factors)	3.000000e-11
GCST009174_2	Response to (pegylated) interferon in chronic hepatitis B	1.000000e-06
GCST90002404_494	Red cell distribution width	2.000000e-29
GCST90011900_60	Serum alkaline phosphatase levels	2.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0600040	plasma clozapine-to-N-desmethylclozapine ratio measurement
EFO:0007859	response to interferon
EFO:0009188	Red cell distribution width
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537362	Immunodeficiency syndrome, variable (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724665 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects expression, decreases expression, affects cotreatment	5
bisphenol A	affects expression, decreases expression	4
Valproic Acid	affects expression, decreases expression, increases expression	4
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
Resveratrol	affects cotreatment, increases expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
lasiocarpine	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	decreases expression, increases activity, affects binding	1
deoxynivalenol	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
beta-glycerophosphoric acid	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
phenethyl isothiocyanate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
K 7174	decreases expression	1
bazedoxifene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697791	Binding	Inhibition of HELLS (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1DN	Abcam HCT 116 HELLS KO	Cancer cell line	Male
CVCL_B1TH	Abcam HeLa HELLS KO	Cancer cell line	Female
CVCL_SR25	HAP1 HELLS (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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