SPPL2A

signal peptide peptidase like 2A, the group of Peptidase family A22

Basic information

Region (hg38): 15:50702265-50765948

Links

ENSG00000138600 ∙ NCBI:84888 ∙ OMIM:608238 ∙ HGNC:30227 ∙ Uniprot:Q8TCT8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• immunodeficiency 86 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 86	AR	Allergy/Immunology/Infectious	The condition involves susceptibility to mycobacterial disease after BCG vaccine, and susbequent localized mycobacterial lymphadenopathy is amenable to treatment	Allergy/Immunology/Infectious	23472171; 30127434

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPPL2A gene.

• not provided (196 variants)
• Inborn genetic diseases (20 variants)
• not specified (5 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPPL2A 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			2	29	3	34
missense			100	5	4	109
nonsense			2			2
start loss			1			1
frameshift			3			3
inframe indel			1			1
splice donor/acceptor (+/-2bp)			3			3
splice region			8	10	5	23
non coding			2	27	8	37
Total	0	0	114	61	15

Variants in SPPL2A

This is a list of pathogenic ClinVar variants found in the SPPL2A region.

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

Position	Type	Phenotype	Significance	ClinVar
15-50707805-G-A			Uncertain significance (Sep 10, 2023)
15-50707809-G-C			Benign (Jan 29, 2024)
15-50707817-G-C			Uncertain significance (Nov 14, 2020)
15-50707846-T-C			Uncertain significance (Jun 23, 2022)
15-50707853-C-T			Uncertain significance (Nov 28, 2023)
15-50707880-C-A			Likely benign (Mar 11, 2022)
15-50707893-C-A			Likely benign (Oct 29, 2023)
15-50707894-G-A			Likely benign (Sep 13, 2023)
15-50719921-C-T			Likely benign (Apr 03, 2021)
15-50719927-T-C			Likely benign (Aug 27, 2023)
15-50719939-C-A			Uncertain significance (Jan 16, 2022)
15-50719948-T-C			Uncertain significance (Jan 20, 2023)
15-50719955-T-C			Likely benign (Jan 27, 2024)
15-50719969-T-G			Uncertain significance (Dec 04, 2023)
15-50719980-C-T		not specified	Uncertain significance (Nov 20, 2023)
15-50719981-G-A			Uncertain significance (Nov 28, 2023)
15-50719997-T-C			Likely benign (Nov 27, 2023)
15-50720004-G-C			Benign (Jan 31, 2024)
15-50720013-G-C			Uncertain significance (Nov 13, 2023)
15-50720018-A-T			Likely benign (Oct 25, 2022)
15-50720019-G-A			Uncertain significance (Mar 20, 2023)
15-50720026-A-C			Uncertain significance (Aug 23, 2023)
15-50720035-G-C			Uncertain significance (Sep 19, 2023)
15-50720048-C-T			Likely benign (Mar 30, 2023)
15-50720056-T-C		SPPL2A-related disorder	Uncertain significance (Oct 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPPL2A	protein_coding	protein_coding	ENST00000261854	15	58500

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0290	0.971	125718	0	25	125743	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.929	219	261	0.838	0.0000122	3380
Missense in Polyphen		56	77.808	0.71972		1022
Synonymous	0.721	79	87.6	0.902	0.00000431	985
Loss of Function	3.44	8	27.4	0.292	0.00000132	356

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000184	0.000182
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000546	0.0000544
Finnish	0.000142	0.000139
European (Non-Finnish)	0.000134	0.000132
Middle Eastern	0.0000546	0.0000544
South Asian	0.0000353	0.0000327
Other	0.000170	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing (PubMed:16829952, PubMed:16829951, PubMed:17557115, PubMed:17965014). Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus (PubMed:16829952). Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD) (PubMed:17557115). May play a role in the regulation of innate and adaptive immunity (PubMed:16829952). Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis (PubMed:23132852). {ECO:0000269|PubMed:16829951, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:17965014, ECO:0000269|PubMed:23132852}.

Recessive Scores

• pRec: 0.118

Intolerance Scores

• loftool: 0.633
• rvis_EVS: 0.97
• rvis_percentile_EVS: 90.34

Haploinsufficiency Scores

• pHI: 0.512
• hipred: N
• hipred_score: 0.492
• ghis: 0.400

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sppl2a
• Phenotype: cellular phenotype; hematopoietic system phenotype; immune system phenotype

Gene ontology

• Biological process: membrane protein ectodomain proteolysis;regulation of tumor necrosis factor-mediated signaling pathway;membrane protein intracellular domain proteolysis;membrane protein proteolysis;regulation of immune response
• Cellular component: lysosomal membrane;late endosome;plasma membrane;membrane;Golgi-associated vesicle membrane;late endosome membrane;intracellular membrane-bounded organelle;extracellular exosome;integral component of cytoplasmic side of endoplasmic reticulum membrane;integral component of lumenal side of endoplasmic reticulum membrane
• Molecular function: protein binding;aspartic endopeptidase activity, intramembrane cleaving;protein homodimerization activity