PSAP

prosaposin, the group of Receptor ligands

Basic information

Region (hg38): 10:71816298-71851251

Previous symbols: [ "SAP1", "GLBA", "SAP2" ]

Links

ENSG00000197746 ∙ NCBI:5660 ∙ OMIM:176801 ∙ HGNC:9498 ∙ Uniprot:P07602 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Krabbe disease due to saposin A deficiency (Definitive), mode of inheritance: AR
• Krabbe disease due to saposin A deficiency (Strong), mode of inheritance: AR
• combined PSAP deficiency (Strong), mode of inheritance: AR
• Gaucher disease due to saposin C deficiency (Strong), mode of inheritance: AR
• metachromatic leukodystrophy due to saposin B deficiency (Strong), mode of inheritance: AR
• Gaucher disease due to saposin C deficiency (Moderate), mode of inheritance: AR
• metachromatic leukodystrophy due to saposin B deficiency (Moderate), mode of inheritance: AR
• combined PSAP deficiency (Supportive), mode of inheritance: AR
• Parkinson disease 24, autosomal dominant, susceptibility to (Limited), mode of inheritance: Unknown
• combined PSAP deficiency (Strong), mode of inheritance: AR
• Gaucher disease due to saposin C deficiency (Strong), mode of inheritance: AR
• Krabbe disease due to saposin A deficiency (Limited), mode of inheritance: AR
• metachromatic leukodystrophy due to saposin B deficiency (Strong), mode of inheritance: AR
• metachromatic leukodystrophy due to saposin B deficiency (Definitive), mode of inheritance: AR
• Krabbe disease due to saposin A deficiency (Moderate), mode of inheritance: AR
• Gaucher disease due to saposin C deficiency (Definitive), mode of inheritance: AR
• combined PSAP deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Parkinson disease 24, autosomal dominant, susceptibility to	AD	Neurologic	Individuals with Parkinson disease may respond to levodopa	Biochemical; Gastrointestinal; Musculoskeletal; Neurologic	41211; 6126151; 2060627; 3024666; 2615292; 2514102; 2764035; 1371116; 8460394; 8554069; 9672525; 9930900; 10682309; 11309366; 15856305; 15773042; 17919309; 19267410; 19955343; 20484222; 22652185
BMT has been described for some allelic conditions; The evidence of the association of variants with Parkinson disease is unclear

ClinVar

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

• Sphingolipid activator protein 1 deficiency (33 variants)
• not provided (4 variants)
• Metachromatic leukodystrophy (2 variants)
• Combined PSAP deficiency (2 variants)
• Gaucher disease due to saposin C deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PSAP 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			1	232	2	235
missense	2	8	197	4	1	212
nonsense	11	1				12
start loss	3					3
frameshift	16	1				17
inframe indel		1	4			5
splice donor/acceptor (+/-2bp)	2	19				21
splice region			14	49	1	64
non coding	1		17	164	46	228
Total	35	30	219	400	49

Highest pathogenic variant AF is 0.0000131

Variants in PSAP

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

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

Position	Type	Phenotype	Significance	ClinVar
10-71816433-G-A		Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Gaucher disease due to saposin C deficiency • Krabbe disease due to saposin A deficiency	Uncertain significance (Jan 13, 2018)
10-71816506-T-C		Krabbe disease due to saposin A deficiency • Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Gaucher disease due to saposin C deficiency	Uncertain significance (Jan 13, 2018)
10-71816550-C-T		Gaucher disease due to saposin C deficiency • Sphingolipid activator protein 1 deficiency • Retinitis pigmentosa-deafness syndrome • Combined PSAP deficiency • Krabbe disease due to saposin A deficiency • Hearing loss, autosomal recessive	Benign/Likely benign (May 14, 2021)
10-71816582-G-A		Gaucher disease due to saposin C deficiency • Combined PSAP deficiency • Krabbe disease due to saposin A deficiency • Sphingolipid activator protein 1 deficiency	Uncertain significance (Jan 13, 2018)
10-71816654-G-A		Gaucher disease due to saposin C deficiency • Sphingolipid activator protein 1 deficiency • Combined PSAP deficiency • Krabbe disease due to saposin A deficiency	Uncertain significance (Jan 13, 2018)
10-71816666-C-T		Krabbe disease due to saposin A deficiency • Sphingolipid activator protein 1 deficiency • Combined PSAP deficiency • Gaucher disease due to saposin C deficiency	Benign (May 22, 2021)
10-71816704-C-T		Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Krabbe disease due to saposin A deficiency • Gaucher disease due to saposin C deficiency	Conflicting classifications of pathogenicity (Jan 13, 2018)
10-71816845-T-C		Sphingolipid activator protein 1 deficiency • Gaucher disease due to saposin C deficiency • Combined PSAP deficiency • Krabbe disease due to saposin A deficiency	Uncertain significance (Jan 13, 2018)
10-71816867-C-G		Krabbe disease due to saposin A deficiency • Gaucher disease due to saposin C deficiency • Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency	Uncertain significance (Jan 13, 2018)
10-71816915-C-T		Sphingolipid activator protein 1 deficiency • Krabbe disease due to saposin A deficiency • Combined PSAP deficiency • Gaucher disease due to saposin C deficiency	Uncertain significance (Jan 13, 2018)
10-71817065-T-C		Krabbe disease due to saposin A deficiency • Combined PSAP deficiency • Gaucher disease due to saposin C deficiency • Sphingolipid activator protein 1 deficiency	Conflicting classifications of pathogenicity (Jan 12, 2018)
10-71817095-G-A		Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Krabbe disease due to saposin A deficiency • Gaucher disease due to saposin C deficiency	Uncertain significance (Jan 13, 2018)
10-71817165-C-T		Krabbe disease due to saposin A deficiency • Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Gaucher disease due to saposin C deficiency	Uncertain significance (Jan 12, 2018)
10-71817203-C-G		Usher syndrome type 1D • Combined PSAP deficiency • Gaucher disease due to saposin C deficiency • Autosomal recessive nonsyndromic hearing loss 12 • Sphingolipid activator protein 1 deficiency • Krabbe disease due to saposin A deficiency	Uncertain significance (Jan 13, 2018)
10-71817319-G-C		Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Gaucher disease due to saposin C deficiency • Krabbe disease due to saposin A deficiency	Conflicting classifications of pathogenicity (Jul 09, 2018)
10-71817328-G-A		Krabbe disease due to saposin A deficiency • Combined PSAP deficiency • Gaucher disease due to saposin C deficiency • Sphingolipid activator protein 1 deficiency	Uncertain significance (Jan 13, 2018)
10-71817351-G-A		Combined PSAP deficiency • Sphingolipid activator protein 1 deficiency • Gaucher disease due to saposin C deficiency • Krabbe disease due to saposin A deficiency	Uncertain significance (Jan 13, 2018)
10-71817368-G-A		Combined PSAP deficiency • Gaucher disease due to saposin C deficiency • Krabbe disease due to saposin A deficiency • Sphingolipid activator protein 1 deficiency	Uncertain significance (Jan 13, 2018)
10-71817432-T-C		Krabbe disease due to saposin A deficiency • Combined PSAP deficiency • Gaucher disease due to saposin C deficiency • Sphingolipid activator protein 1 deficiency	Conflicting classifications of pathogenicity (Jan 12, 2018)
10-71817454-T-C		Sphingolipid activator protein 1 deficiency	Uncertain significance (May 26, 2022)
10-71817456-G-A		Sphingolipid activator protein 1 deficiency	Likely benign (Aug 03, 2020)
10-71817457-C-T		Sphingolipid activator protein 1 deficiency	Uncertain significance (Jul 12, 2022)
10-71817458-G-A		Sphingolipid activator protein 1 deficiency	Uncertain significance (Aug 16, 2022)
10-71817459-T-C		Metachromatic leukodystrophy	Uncertain significance (Apr 11, 2020)
10-71817468-C-T		Sphingolipid activator protein 1 deficiency	Likely benign (Oct 31, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PSAP	protein_coding	protein_coding	ENST00000394936	14	35072

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.991	0.00949	125739	0	9	125748	0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.525	314	289	1.09	0.0000176	3458
Missense in Polyphen		72	82.713	0.87048		1083
Synonymous	-1.34	137	118	1.16	0.00000847	991
Loss of Function	4.30	3	27.2	0.110	0.00000121	343

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000185	0.000185
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000529	0.0000527
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate.; FUNCTION: Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12).; FUNCTION: Saposins are specific low-molecular mass non-enzymic proteins, they participate in the lysosomal degradation of sphingolipids, which takes place by the sequential action of specific hydrolases.
• Disease: DISEASE: Combined saposin deficiency (CSAPD) [MIM:611721]: Due to absence of all saposins, leading to a fatal storage disorder with hepatosplenomegaly and severe neurological involvement. {ECO:0000269|PubMed:11309366, ECO:0000269|PubMed:1371116}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukodystrophy metachromatic due to saposin-B deficiency (MLD-SAPB) [MIM:249900]: An atypical form of metachromatic leukodystrophy. It is characterized by tissue accumulation of cerebroside-3-sulfate, demyelination, periventricular white matter abnormalities, peripheral neuropathy. Additional neurological features include dysarthria, ataxic gait, psychomotor regression, seizures, cognitive decline and spastic quadriparesis. {ECO:0000269|PubMed:10196694, ECO:0000269|PubMed:10682309, ECO:0000269|PubMed:2019586, ECO:0000269|PubMed:2302219, ECO:0000269|PubMed:2320574}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gaucher disease, atypical, due to saposin C deficiency (AGD) [MIM:610539]: A disease characterized by marked glucosylceramide accumulation in the spleen without having a deficiency of glucosylceramide-beta glucosidase characteristic of classic Gaucher disease. Gaucher disease is a lysosomal storage disorder characterized by skeletal deterioration, hepatosplenomegaly, and organ dysfunction. There are several subtypes based on the presence and severity of neurological involvement. {ECO:0000269|PubMed:17919309, ECO:0000269|PubMed:2060627}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Krabbe disease, atypical, due to saposin A deficiency (AKRD) [MIM:611722]: A disorder of galactosylceramide metabolism. Clinical features include neurologic regression around age 3 months, loss of spontaneous movements, hyporeflexia, generalized brain atrophy, and diffuse white matter dysmyelination. {ECO:0000269|PubMed:15773042}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in PSAP saposin-D region are found in a variant of Tay-Sachs disease (GM2-gangliosidosis).
• Pathway: Lysosome - Homo sapiens (human);Signaling by GPCR;Neutrophil degranulation;Signal Transduction;Metabolism of lipids;Innate Immune System;Immune System;Metabolism;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Hemostasis;G alpha (i) signalling events;Glycosphingolipid metabolism;Sphingolipid metabolism;GPCR downstream signalling (Consensus)

Recessive Scores

• pRec: 0.406

Intolerance Scores

• loftool: 0.0907
• rvis_EVS: -1
• rvis_percentile_EVS: 8.47

Haploinsufficiency Scores

• pHI: 0.201
• hipred: Y
• hipred_score: 0.594
• ghis: 0.556

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.855

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Psap
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; vision/eye phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype

Gene ontology

• Biological process: platelet degranulation;corneocyte development;galactosylceramide catabolic process;glycosphingolipid metabolic process;lipid transport;G protein-coupled receptor signaling pathway;adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway;sensory perception of sound;regulation of autophagy;regulation of lipid metabolic process;myelination;neutrophil degranulation;positive regulation of MAPK cascade;neuromuscular process controlling balance;positive regulation of hydrolase activity;micturition;prostate gland growth;epithelial cell differentiation involved in prostate gland development;cellular response to organic substance;cochlea development;walking behavior;negative regulation of hydrogen peroxide-induced cell death;cornified envelope assembly;ganglioside GM1 transport to membrane
• Cellular component: extracellular region;extracellular space;lysosome;lysosomal membrane;plasma membrane;azurophil granule membrane;lysosomal lumen;intracellular membrane-bounded organelle;collagen-containing extracellular matrix;extracellular exosome
• Molecular function: G protein-coupled receptor binding;beta-galactosidase activity;protein binding;phospholipid binding;enzyme activator activity;lipid binding;protein homodimerization activity;ganglioside GM1 binding;ganglioside GM2 binding;ganglioside GM3 binding;ganglioside GT1b binding;ganglioside GP1c binding