SMPD4

sphingomyelin phosphodiesterase 4

Basic information

Region (hg38): 2:130151391-130182750

Links

ENSG00000136699 ∙ NCBI:55627 ∙ OMIM:610457 ∙ HGNC:32949 ∙ Uniprot:Q9NXE4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (Moderate), mode of inheritance: AR
• neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies	AR	Cardiovascular	Among other features, individuals have been described with cardiac anomalies, including structural defects as well as cardiomyopathy, and prompt diagnosis may allow early management of these issues and sequelae	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic	31495489

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMPD4 gene.

• Inborn genetic diseases (61 variants)
• Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (27 variants)
• not provided (21 variants)
• Abnormal cerebral morphology (2 variants)
• not specified (2 variants)
• See cases (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMPD4 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				8	3	11
missense		1	61	3	1	66
nonsense		3	1			4
start loss						0
frameshift	2	3	1			6
inframe indel			2			2
splice donor/acceptor (+/-2bp)	3	1				4
splice region	1		1	1		3
non coding	1		7		3	11
Total	6	8	72	11	7

Highest pathogenic variant AF is 0.0000131

Variants in SMPD4

This is a list of pathogenic ClinVar variants found in the SMPD4 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-130152561-C-A		Inborn genetic diseases	Uncertain significance (May 10, 2023)
2-130152571-T-C		Inborn genetic diseases	Uncertain significance (Feb 07, 2023)
2-130152581-C-T		Inborn genetic diseases	Uncertain significance (Oct 25, 2023)
2-130152582-G-A			Likely benign (Oct 01, 2023)
2-130152637-G-A		Inborn genetic diseases	Uncertain significance (Nov 02, 2023)
2-130152638-T-C		Inborn genetic diseases	Likely benign (Nov 21, 2023)
2-130152663-CAG-C		Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies	Uncertain significance (May 06, 2021)
2-130152664-A-G		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
2-130152671-C-T		Inborn genetic diseases	Uncertain significance (Aug 13, 2021)
2-130152673-A-G		Inborn genetic diseases	Uncertain significance (Mar 13, 2023)
2-130152674-CGAA-C		Inborn genetic diseases	Uncertain significance (Mar 23, 2022)
2-130152706-C-T			Uncertain significance (Jun 16, 2022)
2-130152705-C-CCGGTAACTGCCCAGGAAG		Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies	Uncertain significance (Aug 21, 2023)
2-130152707-G-A		Inborn genetic diseases	Uncertain significance (Mar 14, 2023)
2-130152709-T-C		Inborn genetic diseases	Uncertain significance (Jan 29, 2024)
2-130152714-G-A			Likely benign (Oct 01, 2023)
2-130152738-G-A			Likely benign (Dec 01, 2023)
2-130152742-C-T		Inborn genetic diseases	Uncertain significance (Jun 29, 2022)
2-130152743-C-T		Inborn genetic diseases	Uncertain significance (Apr 14, 2022)
2-130152746-G-A		Inborn genetic diseases	Uncertain significance (May 08, 2023)
2-130152756-G-A			Benign (Dec 14, 2017)
2-130152778-GGGCTCAGCAGGTGCCTGCT-G		Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies	Likely pathogenic (-)
2-130152814-G-A		Inborn genetic diseases	Uncertain significance (Jan 24, 2024)
2-130152842-G-C		Inborn genetic diseases	Uncertain significance (Nov 03, 2022)
2-130152853-C-T		Inborn genetic diseases	Uncertain significance (Feb 22, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMPD4	protein_coding	protein_coding	ENST00000409031	20	31343

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.71e-19	0.150	125679	0	69	125748	0.000274

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.857	474	530	0.895	0.0000326	5591
Missense in Polyphen		142	155.74	0.9118		1496
Synonymous	-1.42	256	229	1.12	0.0000151	1743
Loss of Function	1.43	35	45.4	0.771	0.00000225	485

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000357	0.000355
Ashkenazi Jewish	0.000211	0.000198
East Asian	0.000229	0.000217
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000339	0.000334
Middle Eastern	0.000229	0.000217
South Asian	0.000302	0.000294
Other	0.000666	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide (PubMed:16517606). May sensitize cells to DNA damage-induced apoptosis (PubMed:18505924). {ECO:0000269|PubMed:16517606, ECO:0000269|PubMed:18505924}.
• Pathway: Sphingolipid metabolism - Homo sapiens (human);Metabolism of lipids;sphingomyelin metabolism/ceramide salvage;Metabolism;Glycosphingolipid metabolism;Glycosphingolipid metabolism;Sphingolipid metabolism (Consensus)

Recessive Scores

• pRec: 0.102

Intolerance Scores

• loftool: 0.0439
• rvis_EVS: -1.39
• rvis_percentile_EVS: 4.31

Haploinsufficiency Scores

• pHI: 0.187
• hipred: Y
• hipred_score: 0.527
• ghis: 0.566

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.519

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Smpd4
• Phenotype: renal/urinary system phenotype; vision/eye 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); normal 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)

Gene ontology

• Biological process: sphingomyelin catabolic process;glycosphingolipid metabolic process;glycerophospholipid catabolic process;ceramide biosynthetic process;cellular response to tumor necrosis factor
• Cellular component: Golgi membrane;endoplasmic reticulum;endoplasmic reticulum membrane;Golgi apparatus;trans-Golgi network;integral component of membrane
• Molecular function: sphingomyelin phosphodiesterase activity;metal ion binding;sphingomyelin phosphodiesterase D activity