GeneBe

SMPD4

protein-coding

sphingomyelin phosphodiesterase 4

Gene summary

The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]

MANE transcript

NM_017951.5

Inheritance

AR

ClinVar variants

P:34U:173B:41

Top phenotype

Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr2:130,151,392-130,182,750

External References & Databases

Ensembl (ENSG00000136699)NCBI Gene (55627)OMIM (610457)HGNC:32949GenCCUniProt (Q9NXE4)AlphaFoldClinVar (SMPD4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~31.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032838

Submitter: PanelApp Australia

neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032838

Submitter: G2P

neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032838

Submitter: Ambry Genetics

neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032838

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesAR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: 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

Refs: 31495489Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMPD4 variants in ClinVar

7 Conditions Cataloged
Inborn genetic diseasesTotal: 148
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomaliesTotal: 46
not providedTotal: 45
not specifiedTotal: 27
Abnormal cerebral morphologyTotal: 2
See casesTotal: 2
SMPD4-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017951.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
32
clinvar
2
clinvar
 35
missense
3
clinvar
162
clinvar
7
clinvar
 172
nonsense
1
clinvar
5
clinvar
3
clinvar
 9
start loss
0
frameshift
4
clinvar
13
clinvar
2
clinvar
 19
splice donor/acceptor (+/-2bp)
4
clinvar
4
clinvar
5
clinvar
 13
Total925173392248

Highest pathogenic variant AF is 0.000040896957

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017951.5RefSeqNP_060421.319MANE Select
ENST00000680298.1EnsemblENSP00000506463.119MANE Select
NM_001171083.2RefSeqNP_001164554.117Standard
NM_017751.4RefSeqNP_060221.219Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Sphingolipid metabolism - Homo sapiens (human)
  • Metabolism of lipids
  • sphingomyelin metabolism/ceramide salvage
  • Metabolism
  • Glycosphingolipid metabolism

Biological Process

  • sphingomyelin catabolic process
  • glycosphingolipid metabolic process
  • glycerophospholipid catabolic process
  • ceramide biosynthetic process
  • cellular response to tumor necrosis factor

Molecular Function

  • sphingomyelin phosphodiesterase activity
  • metal ion binding
  • sphingomyelin phosphodiesterase D activity

Cellular Component

  • Golgi membrane
  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • Golgi apparatus
  • trans-Golgi network

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000409031
Coding exons
20
Length
31343
Individuals with no LoFs
125679
Homozygous LoFs
0
Heterozygous LoFs
69
Defined
125748
p
0.000274
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8574745300.8950.00003265591
Missense (PolyPhen)142155.740.91181496
Synonymous-1.422562291.120.00001511743
Loss of Function1.433545.40.7710.00000225485

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000640.000062rare
Latino/Admixed American0.000290.00029rare
Ashkenazi Jewish0.000210.00020rare
East Asian0.000230.00022rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000340.00033rare
South Asian0.000300.00029rare
Other0.000670.00065rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec
0.102

Intolerance Scores

LoFtool
0.0439
RVIS EVS
-1.39
RVIS percentile EVS
4.31

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.519

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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