SP110

protein-coding

SP110 nuclear body protein, the group of PHD finger proteins|Minor histocompatibility antigens|Bromodomain containing

Gene summary

The nuclear body is a multiprotein complex that may have a role in the regulation of gene transcription. This gene is a member of the SP100/SP140 family of nuclear body proteins and encodes a leukocyte-specific nuclear body component. The protein can function as an activator of gene transcription and may serve as a nuclear hormone receptor coactivator. In addition, it has been suggested that the protein may play a role in ribosome biogenesis and in the induction of myeloid cell differentiation. Alternative splicing has been observed for this gene and three transcript variants, encoding distinct isoforms, have been identified. [provided by RefSeq, Jul 2008]

Previous symbols:

IFI41
IFI75

MANE transcript

NM_080424.4

Inheritance

ClinVar variants

P:46U:257B:147

Top phenotype

Hepatic venoocclusive disease with immunodeficiency

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr2:230,165,186-230,225,729

External References & Databases

Ensembl (ENSG00000135899)

Transcript & Mutation Effects

hg38 • Region Span ~60.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hepatic veno-occlusive disease-immunodeficiency syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009338

Submitter: ClinGen

SP110 was first reported in relation to autosomal recessive hepatic veno-occlusive disease-immunodeficiency syndrome (VODI) in 2006 (Rosicioli et al., PMID: 16648851). VODI is characterized by bacterial infections (including Pneumocystis jirovecii, cytomegalovirus, enterovirus, or mucocutaneous candidiasis), hepatomegaly or hepatic failure, liver biopsy results consistent with sinusoidal obstruction syndrome, hypogammaglobulinemia, low intracellular cytokine production, and usually T-cell immunodeficiency with normal circulating T and B cell counts. Some patients displayed a complex neurological phenotype, however the association with SP110 is not fully understood (PMID: 23448538). The mechanism of pathogenicity appears to be homozygous loss of function. The curation of SP110 related to autosomal recessive VODI includes both case-level and experimental evidence. Seven variants (missense, frameshift, and nonsense) reported in seven probands in four publications (PMIDs: 16648851, 22621957, 23448538, 32395362) are included in this curation. The heterozygous parents of probands were all unaffected. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by its enhanced expression in lymphoid tissue (PMID: 16127175), disruption of which is observed by flow cytometry of patient T cell blasts (PMID: 28825155). Additionally, functional alteration is reported in patient cells (PMID: 22621957), such that there is an impairment of B cells to produce IgM, IgG, and IgA. The impaired survival and activation of B cells in vitro most likely explains the hypogammaglobulinemia that is typical of patients with VODI. In summary, there is definitive evidence supporting the relationship between SP110 and autosomal recessive hepatic veno-occlusive disease-immunodeficiency syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

hepatic veno-occlusive disease-immunodeficiency syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009338

Submitter: Labcorp Genetics (formerly Invitae)

hepatic veno-occlusive disease-immunodeficiency syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009338

Submitter: Ambry Genetics

hepatic veno-occlusive disease-immunodeficiency syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009338

Submitter: Orphanet

hepatic veno-occlusive disease-immunodeficiency syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009338

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hepatic venoocclusive disease with immunodeficiencyAR

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Mortality is high if the condition is unrecognized; interventions include intravenous immunoglobulin and infectious prophylaxis (Pneumocystis jerovici)

Refs: 16648851; 17510920; 22621957; 22982295

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SP110 variants in ClinVar

6 Conditions Cataloged

Hepatic veno-occlusive disease-immunodeficiency syndromeTotal: 482

Inborn genetic diseasesTotal: 113

not specifiedTotal: 40

not providedTotal: 32

SP110-related disorderTotal: 19

Mycobacterium tuberculosis, susceptibility toTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_080424.4. 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			6 clinvar	116 clinvar	3 clinvar	125
missense	1 clinvar		237 clinvar	24 clinvar	3 clinvar	265
nonsense	4 clinvar	10 clinvar	2 clinvar	1 clinvar		17
start loss			1 clinvar			1
frameshift	16 clinvar	5 clinvar	3 clinvar			24
splice donor/acceptor (+/-2bp)		10 clinvar	8 clinvar			18
Total	21	25	257	141	6	450

Highest pathogenic variant AF is 0.000114628165

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_080424.4	RefSeq	NP_536349.3	18	MANE Select
ENST00000258381.11	Ensembl	ENSP00000258381.6	18	MANE Select
NM_001185015.2	RefSeq	NP_001171944.1	15	Standard
NM_001378442.1	RefSeq	NP_001365371.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
viral process

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258381
Coding exons: 18
Length: 58436
Individuals with no LoFs: 125659
Homozygous LoFs: 0
Heterozygous LoFs: 89
Defined: 125748
p: 0.000354

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.335	355	373	0.951	0.0000208	4695
Missense (PolyPhen)		24	23.936	1.0027		232
Synonymous	-0.121	141	139	1.01	0.00000863	1307
Loss of Function	1.83	28	40.6	0.689	0.00000221	493

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.0016	0.0016	notable
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor. May be a nuclear hormone receptor coactivator. Enhances transcription of genes with retinoic acid response elements (RARE).;
Disease: DISEASE: Hepatic venoocclusive disease with immunodeficiency (VODI) [MIM:235550]: Autosomal recessive primary immunodeficiency associated with hepatic vascular occlusion and fibrosis. The immunodeficiency is characterized by severe hypogammaglobulinemia, combined T and B-cell immunodeficiency, absent lymph node germinal centers, and absent tissue plasma cells. {ECO:0000269|PubMed:16648851}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.496
RVIS EVS: 0.54
RVIS percentile EVS: 81.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.682

Gene Damage Prediction

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