SMPD1

sphingomyelin phosphodiesterase 1

Basic information

Region (hg38): 11:6390440-6394998

Links

ENSG00000166311 ∙ NCBI:6609 ∙ OMIM:607608 ∙ HGNC:11120 ∙ Uniprot:P17405 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Niemann-Pick disease (Definitive), mode of inheritance: AR
• Niemann-Pick disease type A (Definitive), mode of inheritance: AR
• Niemann-Pick disease type A (Strong), mode of inheritance: AR
• Niemann-Pick disease type B (Strong), mode of inheritance: AR
• Niemann-Pick disease type A (Supportive), mode of inheritance: AR
• Niemann-Pick disease type B (Supportive), mode of inheritance: AR
• Niemann-Pick disease type B (Strong), mode of inheritance: AR
• acid sphingomyelinase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Niemann-Pick disease, type A; Niemann-Pick disease, type B	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Neurologic; Ophthalmologic; Pulmonary	13516139; 2023926; 1301192; 1618760; 8664904; 12369017; 15877209; 16434659; 17360762; 17632693; 18815062; 19050888; 19405096; 20301544; 20386867; 22613662
It has been suggested that it could be useful to screen for NPB in heart disease clinics (for patients with very low HDL), or in endocrinology clinics (in individuals with growth retardation)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMPD1 gene.

• Niemann-Pick disease, type B;Niemann-Pick disease, type A (59 variants)
• Niemann-Pick disease, type A (45 variants)
• Niemann-Pick disease, type A;Niemann-Pick disease, type B (40 variants)
• not provided (22 variants)
• Sphingomyelin/cholesterol lipidosis (16 variants)
• Niemann-Pick disease, type B (12 variants)
• not specified (5 variants)
• Niemann-pick disease, intermediate, protracted neurovisceral (2 variants)
• SMPD1-related disorder (2 variants)
• Inborn genetic diseases (1 variants)
• See cases (1 variants)
• Acid sphingomyelinase deficiency (1 variants)
• Intellectual disability (1 variants)
• Niemann-Pick disease, type C1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMPD1 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	4	287	4	297
missense	23	106	133	14	3	279
nonsense	26	23				49
start loss	1					1
frameshift	64	59	2	1		126
inframe indel	2	2	15	4	6	29
splice donor/acceptor (+/-2bp)	2	15		1		18
splice region	1		1	16		18
non coding	1	2	7	47	9	66
Total	119	209	161	354	22

Highest pathogenic variant AF is 0.00726

Variants in SMPD1

This is a list of pathogenic ClinVar variants found in the SMPD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-6390467-G-A			Likely benign (Aug 28, 2018)
11-6390554-G-C		Niemann-Pick disease, type A	Likely benign (Apr 27, 2017)
11-6390560-A-T		Niemann-Pick disease, type A	Uncertain significance (Jan 13, 2018)
11-6390587-G-A			Uncertain significance (May 25, 2018)
11-6390601-GC-G		Niemann-Pick disease, type A • Niemann-Pick disease, type B;Niemann-Pick disease, type A	Pathogenic (Jan 16, 2024)
11-6390604-C-T		Niemann-Pick disease, type B;Niemann-Pick disease, type A	Likely benign (Jul 30, 2023)
11-6390606-G-A		Niemann-Pick disease, type B;Niemann-Pick disease, type A • Sphingomyelin/cholesterol lipidosis • SMPD1-related disorder • Niemann-Pick disease, type A	Conflicting classifications of pathogenicity (Jan 31, 2024)
11-6390605-C-CGCTTTGTGAT		Niemann-Pick disease, type A	Likely pathogenic (Jan 04, 2024)
11-6390607-C-G		Niemann-Pick disease, type A;Niemann-Pick disease, type B	Likely benign (Oct 07, 2023)
11-6390607-C-T		Niemann-Pick disease, type A;Niemann-Pick disease, type B	Likely benign (Sep 09, 2020)
11-6390608-T-C		Sphingomyelin/cholesterol lipidosis	Uncertain significance (Oct 14, 2020)
11-6390614-G-GCGTCACTC		Niemann-Pick disease, type A	Likely pathogenic (May 25, 2023)
11-6390622-C-A		Niemann-Pick disease, type B;Niemann-Pick disease, type A	Likely benign (Dec 31, 2022)
11-6390624-G-T		Sphingomyelin/cholesterol lipidosis	Uncertain significance (Apr 14, 2020)
11-6390626-C-T		Niemann-Pick disease, type A • Niemann-Pick disease, type B;Niemann-Pick disease, type A • SMPD1-related disorder	Pathogenic/Likely pathogenic (Jan 03, 2024)
11-6390628-G-A		Niemann-Pick disease, type A;Niemann-Pick disease, type B	Likely benign (Jan 16, 2021)
11-6390631-C-T		Niemann-Pick disease, type B;Niemann-Pick disease, type A	Likely benign (Jul 16, 2023)
11-6390633-GC-G		Niemann-Pick disease, type B;Niemann-Pick disease, type A • Niemann-Pick disease, type A	Pathogenic/Likely pathogenic (Apr 11, 2022)
11-6390634-C-T		Niemann-Pick disease, type A;Niemann-Pick disease, type B	Likely benign (Aug 25, 2020)
11-6390637-C-T		Niemann-Pick disease, type A;Niemann-Pick disease, type B • SMPD1-related disorder	Conflicting classifications of pathogenicity (Sep 03, 2023)
11-6390640-GT-G		Niemann-Pick disease, type A;Niemann-Pick disease, type B	Pathogenic (Mar 09, 2022)
11-6390643-C-T		Niemann-Pick disease, type B;Niemann-Pick disease, type A	Likely benign (Aug 04, 2022)
11-6390647-C-A		Niemann-Pick disease, type B;Niemann-Pick disease, type A	Likely benign (Aug 04, 2023)
11-6390648-G-A		Niemann-Pick disease, type B;Niemann-Pick disease, type A	Uncertain significance (Apr 04, 2022)
11-6390650-G-T		Niemann-Pick disease, type A • Niemann-Pick disease, type B;Niemann-Pick disease, type A	Pathogenic/Likely pathogenic (Jun 29, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMPD1	protein_coding	protein_coding	ENST00000342245	6	4574

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.89e-10	0.545	125673	0	75	125748	0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0974	382	377	1.01	0.0000219	4010
Missense in Polyphen		124	135.09	0.91793		1531
Synonymous	-0.995	175	159	1.10	0.00000920	1369
Loss of Function	1.23	18	24.6	0.731	0.00000129	241

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000125	0.000123
Ashkenazi Jewish	0.00139	0.00139
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000314	0.000308
Middle Eastern	0.00	0.00
South Asian	0.000719	0.000719
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Converts sphingomyelin to ceramide (PubMed:1840600, PubMed:18815062, PubMed:27659707, PubMed:25920558). Also has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol. {ECO:0000269|PubMed:1840600, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:25920558, ECO:0000269|PubMed:27659707, ECO:0000305}.; FUNCTION: Isoform 3 lacks residues that bind the cofactor Zn(2+) and has no enzyme activity. {ECO:0000269|PubMed:1840600, ECO:0000305}.
• Disease: DISEASE: Niemann-Pick disease A (NPDA) [MIM:257200]: An early- onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms. The severe neurological disorders and pulmonary infections lead to an early death, often around the age of four. Clinical features are variable. A phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. {ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1391960, ECO:0000269|PubMed:15221801, ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:1718266, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:2023926, ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:23430884, ECO:0000269|PubMed:26499107, ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:8680412, ECO:0000269|PubMed:8693491, ECO:0000269|PubMed:9266408}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Niemann-Pick disease B (NPDB) [MIM:607616]: A late-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Clinical signs involve only visceral organs. The most constant sign is hepatosplenomegaly which can be associated with pulmonary symptoms. Patients remain free of neurologic manifestations. However, a phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. In Niemann-Pick disease type B, onset of the first symptoms occurs in early childhood and patients can survive into adulthood. {ECO:0000269|PubMed:12369017, ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1301192, ECO:0000269|PubMed:15241805, ECO:0000269|PubMed:16010684, ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:16472269, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:1885770, ECO:0000269|PubMed:19050888, ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:21621718, ECO:0000269|PubMed:22613662, ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:23430512, ECO:0000269|PubMed:25920558, ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:26499107, ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:8051942, ECO:0000269|PubMed:8664904}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Lysosome - Homo sapiens (human);Necroptosis - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Sphingolipid metabolism - Homo sapiens (human);Ovarian Infertility Genes;phospholipids as signalling intermediaries;Metabolism of lipids;sphingomyelin metabolism/ceramide salvage;Metabolism;ceramide signaling pathway;Glycosphingolipid metabolism;Glycosphingolipid metabolism;Sphingolipid metabolism;TRAIL signaling pathway;TNF receptor signaling pathway ;IL2 signaling events mediated by PI3K;FAS (CD95) signaling pathway;Ceramide signaling pathway (Consensus)

Recessive Scores

• pRec: 0.414

Intolerance Scores

• loftool: 0.0435
• rvis_EVS: 1.72
• rvis_percentile_EVS: 96.48

Haploinsufficiency Scores

• pHI: 0.121
• hipred: N
• hipred_score: 0.396
• ghis: 0.404

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.947

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Smpd1
• Phenotype: hematopoietic system phenotype; reproductive system 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); respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system 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); growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: sphingomyelin metabolic process;sphingomyelin catabolic process;glycosphingolipid metabolic process;signal transduction;nervous system development;termination of signal transduction;positive regulation of protein dephosphorylation;response to cocaine;positive regulation of apoptotic process;negative regulation of MAP kinase activity;ceramide biosynthetic process
• Cellular component: extracellular space;lysosome;endosome;plasma membrane;lamellar body;lysosomal lumen;extracellular exosome
• Molecular function: sphingomyelin phosphodiesterase activity;protein binding;phosphoric diester hydrolase activity;zinc ion binding;hydrolase activity, acting on glycosyl bonds;acid sphingomyelin phosphodiesterase activity