HELLS

protein-coding

helicase, lymphoid specific, the group of DNA helicases

Gene summary

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. [provided by RefSeq, Jan 2014]

MANE transcript

NM_018063.5

Inheritance

ClinVar variants

P:21U:160B:142

Top phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr10:94,545,329-94,613,905

External References & Databases

Ensembl (ENSG00000119969)

Transcript & Mutation Effects

hg38 • Region Span ~68.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency-centromeric instability-facial anomalies syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014829

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency-centromeric instability-facial anomalies syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000133

Submitter: Orphanet

immunodeficiency-centromeric instability-facial anomalies syndrome 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014829

Submitter: ClinGen

*HELLS* was first reported in relation to autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome 4 in 2015 (Thijssen et al., PMID: 26216346). This condition is characterized by recurrent infection, dysmorphic facial features, developmental delay, cytogenetic abnormalities on chromosomes 1,9, and 16, and hypomethylation of alpha satellite regions. Six variants (frameshift, in frame deletion, missense, nonsense, and splice site) have been reported in five probands in two publications (PMIDs: 26216346, 30511102). Variants segregated with disease in two families. Heterozygous parents and siblings were unaffected. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by biochemical function, GTEx bulk tissue expression showing that HELLS is greatly expressed in EBV transformed lymphocytes and other highly proliferative tissues such as the testis, and a co-immunoprecipitation assay demonstrated that HELLS interacts with CDCA7, which is associated with ICF type 3 (PMIDs:23715323, 36012581, 30307408). Additionally, the gene-disease relationship is supported by several cell culture and animal models, including a conditional mouse model which showed that knocked out LSH (mouse orthologue of HELLS) recapitulated a core immunological phenotype of reduced Ig levels (PMID: 32727902). Other cell culture models demonstrated that knock down HELLS recapitulated phenotypes of centromeric hypomethylation (PMID:26216346), while another model suggests HELLS may effect NHEJ, which may reflect a deficiency in class switch recombination observed in patients (PMID:32727902). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen SCID-CID GCEP on 4/20/2023. This gene-disease relationship was re-evaluated on 4/16/2025. As a result of this re-evaluation, no new evidence was identified and the classification did not change (SOP Version 11).

immunodeficiency-centromeric instability-facial anomalies syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014829

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency-centromeric instability-facial anomalies syndrome 4AR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described with recurrent childhood infections, and awareness may allow prompt and aggressive treatment of infections

Refs: 26216346

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HELLS variants in ClinVar

5 Conditions Cataloged

not providedTotal: 417

Inborn genetic diseasesTotal: 64

not specifiedTotal: 49

Immunodeficiency-centromeric instability-facial anomalies syndrome 4Total: 22

HELLS-related disorderTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018063.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	133 clinvar	2 clinvar	137
missense	1 clinvar		154 clinvar	6 clinvar		161
nonsense	8 clinvar					8
start loss			1 clinvar	1 clinvar		2
frameshift	5 clinvar	2 clinvar				7
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	3 clinvar			8
Total	15	6	160	140	2	323

Highest pathogenic variant AF is 0.000009773738

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018063.5	RefSeq	NP_060533.2	22	MANE Select
ENST00000348459.10	Ensembl	ENSP00000239027.7	22	MANE Select
NM_001289067.2	RefSeq	NP_001275996.1	23	Standard
NM_001289068.2	RefSeq	NP_001275997.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hells	Danio rerio	Structure: head Quality: aplastic/hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

hells

Danio rerio

Structure: head

Quality: aplastic/hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis
Apoptosis-related network due to altered Notch3 in ovarian cancer
Apoptotic Signaling Pathway
Validated transcriptional targets of deltaNp63 isoforms

Biological Process

methylation-dependent chromatin silencing
cell cycle
multicellular organism development
maintenance of DNA methylation
pericentric heterochromatin assembly

Molecular Function

helicase activity
protein binding
ATP binding

Cellular Component

chromosome, centromeric region
nucleus
pericentric heterochromatin

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000348459
Coding exons: 22
Length: 68116
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125720
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.99	258	433	0.595	0.0000218	5549
Missense (PolyPhen)		30	135.33	0.22168		1756
Synonymous	-0.145	145	143	1.02	0.00000684	1481
Loss of Function	6.01	7	55.1	0.127	0.00000336	644

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0	0.0	absent
Finnish	0.000095	0.000092	rare
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0.000071	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an essential role in normal development and survival. Involved in regulation of the expansion or survival of lymphoid cells. Required for de novo or maintenance DNA methylation. May control silencing of the imprinted CDKN1C gene through DNA methylation. May play a role in formation and organization of heterochromatin, implying a functional role in the regulation of transcription and mitosis (By similarity). {ECO:0000250|UniProtKB:Q60848}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:26216346}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.323

Intolerance Scores

LoFtool: 0.223
RVIS EVS: 0.02
RVIS percentile EVS: 55.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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