SPPL2A

protein-coding

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

Gene summary

This gene encodes a member of the GXGD family of aspartic proteases, which are transmembrane proteins with two conserved catalytic motifs localized within the membrane-spanning regions, as well as a member of the signal peptide peptidase-like protease (SPPL) family. This protein is expressed in all major adult human tissues and localizes to late endosomal compartments and lysosomal membranes. A pseudogene of this gene also lies on chromosome 15. [provided by RefSeq, Feb 2012]

MANE transcript

NM_032802.4

Inheritance

ClinVar variants

P:3U:224B:81

Top phenotype

Immunodeficiency 86

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr15:50,702,266-50,765,948

External References & Databases

Ensembl (ENSG00000138600)

Transcript & Mutation Effects

hg38 • Region Span ~63.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 86MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030448

Submitter: PanelApp Australia

immunodeficiency 86LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030448

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Immunodeficiency 86AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: The condition involves susceptibility to mycobacterial disease after BCG vaccine, and susbequent localized mycobacterial lymphadenopathy is amenable to treatment

Refs: 23472171; 30127434

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPPL2A variants in ClinVar

4 Conditions Cataloged

not providedTotal: 373

not specifiedTotal: 94

Immunodeficiency 86Total: 3

SPPL2A-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032802.4. 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			3 clinvar	68 clinvar	1 clinvar	72
missense			199 clinvar	10 clinvar	2 clinvar	211
nonsense		1 clinvar	5 clinvar			6
start loss			2 clinvar			2
frameshift			7 clinvar			7
splice donor/acceptor (+/-2bp)	2 clinvar		8 clinvar			10
Total	2	1	224	78	3	308

Highest pathogenic variant AF is 0.000001370107

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_032802.4	RefSeq	NP_116191.2	15	MANE Select
ENST00000261854.10	Ensembl	ENSP00000261854.5	15	MANE Select
NM_001438111.1	RefSeq	NP_001425040.1	16	Standard
NM_001438112.1	RefSeq	NP_001425041.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

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

Molecular Function

protein binding
aspartic endopeptidase activity, intramembrane cleaving
protein homodimerization activity

Cellular Component

lysosomal membrane
late endosome
plasma membrane
membrane
Golgi-associated vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261854
Coding exons: 15
Length: 58500
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125743
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.929	219	261	0.838	0.0000122	3380
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000035	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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