GeneBe

ASAH1

protein-coding

N-acylsphingosine amidohydrolase 1

Gene summary

This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

Previous symbols:
  • ASAH

MANE transcript

NM_177924.5

Inheritance

AR

ClinVar variants

P:131U:307B:158

Top phenotype

Farber lipogranulomatosis; Spinal muscular atrophy with progressive myoclonic epilepsy

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr8:18,055,992-18,084,998

External References & Databases

Ensembl (ENSG00000104763)NCBI Gene (427)OMIM (613468)HGNC:735GenCCUniProt (Q13510)AlphaFoldClinVar (ASAH1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~29.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Farber lipogranulomatosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009218

Submitter: G2P

spinal muscular atrophy-progressive myoclonic epilepsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008045

Submitter: Labcorp Genetics (formerly Invitae)

spinal muscular atrophy-progressive myoclonic epilepsy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008045

Submitter: Orphanet

Farber lipogranulomatosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009218

Submitter: Labcorp Genetics (formerly Invitae)

spinal muscular atrophy-progressive myoclonic epilepsy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008045

Submitter: Genomics England PanelApp

Farber lipogranulomatosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009218

Submitter: Orphanet

ASAH1-related disordersSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800460

Submitter: PanelApp Australia

ASAH1-related sphingolipidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100524

Submitter: ClinGen

The relationship between *ASAH1* and ASAH1-related sphingolipidosis, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of October, 2023. *ASAH1* encodes a member of the acid ceramidase family of proteins. A preproprotein is encoded that undergoes proteolytic processing generating alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, acid ceramidase, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. OMIM disease entities: Farber lipogranulomatosis (MIM: 228000) and Spinal muscular atrophy with progressive myoclonic epilepsy (MIM: 159950). The term "ASAH1-related sphingolipidosis", also referred to as acid ceramidase deficiency in the literature, has been introduced to lump the two disease assertions related to ASAH1. Both Farber lipogranulomatosis and Spinal muscular atrophy form a continuum (PMID: 32449975, 30029679), with progressive myoclonic epilepsy have moderate phenotypic overlap, including a patient with features of both diseases (PMID: 27650050), are inherited in the autosomal recessive manner, and result from biallelic variants in ASAH1 that result in loss of function. *ASAH1* was first reported in relation to autosomal recessive ASAH1-related sphingolipidosis in 1996 (Koch et al, PMID: 8955159). At least 100 missense variants have been reported in human patients. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 11 probands in 6 publications (PMID: 22703880, 28251733, 8955159, 27650050, 24355074, 11241842) showing classic Farber lipogranulomatosis of varying severity, spinal muscular atrophy with progressive myoclonic epilepsy or a blended phenotype of both disorders. Much more evidence is available in the literature, but the maximum score for genetic evidence was reached. The mechanism for disease is expected to be biallelic loss of function. Summary of experimental data (6 points): This gene-disease relationship is supported by in vitro functional studies, model organisms and rescue evidence. Reduction in acid ceramidase activity leads to the accumulation of ceramides in the lysosomes (PMID: 27155573). Zebrafish and mouse models that partially recapitulate the human phenotype have been reported (PMID: 11829492, 23681708, 22703880). Rescue of phenotype by the wild-type gene product has been reported in a knock-in mouse model (PMID: 23681708). In summary, *ASAH1* is definitively associated with autosomal recessive ASAH1-related sphingolipidosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Lysosomal Diseases GCEP on October 4, 2023 (SOP v9). Additional information on prenatal phenotype (added May 1, 2024): Prenatal phenotypes described in the literature in association with ASAH1 include non-immune hydrops fetalis, abnormal cardiac structure, arrhythmia, and bradycardia. Two cases are reported with bi-allelic splicing variants and an exonic deletion (PMID: 8650144, 9128814, 23707712, 37962265). Given the limited reports in the literature the association of ASAH1 with prenatal phenotypes is currently limited.

Farber lipogranulomatosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009218

Submitter: Genomics England PanelApp

spinal muscular atrophy-progressive myoclonic epilepsy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008045

Submitter: G2P

Clinical Genomic Database (CGD)

Farber lipogranulomatosis; Spinal muscular atrophy with progressive myoclonic epilepsyAR

Manifestation: Biochemical; Musculoskeletal; Neurologic; Pulmonary

Intervention: General

Rationale: 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

Comments: HSCT has been described

Refs: 13859108; 6423791; 2983648; 2854742; 3103372; 3130860; 8955159; 8892023; 11241842; 22703880; 24164096; 30029679Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASAH1 variants in ClinVar

16 Conditions Cataloged
not providedTotal: 787
Farber lipogranulomatosisTotal: 109
Inborn genetic diseasesTotal: 45
Spinal muscular atrophy-progressive myoclonic epilepsy syndromeTotal: 39
not specifiedTotal: 38
ASAH1-related disordersTotal: 31
ASAH1-related sphingolipidosisTotal: 2
Self-limited epilepsy with centrotemporal spikesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177924.5. 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
7
clinvar
147
clinvar
 154
missense
11
clinvar
36
clinvar
295
clinvar
9
clinvar
2
clinvar
 353
nonsense
14
clinvar
6
clinvar
1
clinvar
 21
start loss
3
clinvar
2
clinvar
 5
frameshift
22
clinvar
6
clinvar
2
clinvar
 30
splice donor/acceptor (+/-2bp)
4
clinvar
27
clinvar
2
clinvar
 33
Total54773071562596

Highest pathogenic variant AF is 0.00009204772

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 75 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_177924.5RefSeqNP_808592.214MANE Select
ENST00000637790.2EnsemblENSP00000490272.114MANE Select
NM_001127505.3RefSeqNP_001120977.114Standard
NM_001363743.2RefSeqNP_001350672.112Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
asah1bDanio rerio

Structure: primary motor neuron

Quality: decreased branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)
  • Sphingolipid signaling pathway - Homo sapiens (human)
  • Sphingolipid metabolism - Homo sapiens (human)
  • Sphingolipid Metabolism
  • Signal Transduction of S1P Receptor

Biological Process

  • ceramide metabolic process
  • glycosphingolipid metabolic process
  • neutrophil degranulation

Molecular Function

  • catalytic activity
  • hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds
  • N-acylsphingosine amidohydrolase activity
  • ceramidase activity

Cellular Component

  • extracellular region
  • extracellular space
  • lysosomal lumen
  • extracellular exosome
  • tertiary granule lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000381733
Coding exons
14
Length
28561
Individuals with no LoFs
125704
Homozygous LoFs
0
Heterozygous LoFs
44
Defined
125748
p
0.000175
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-2.213102181.420.00001082669
Missense (PolyPhen)8369.8791.1878866
Synonymous-0.05197675.41.010.00000376747
Loss of Function0.8462125.60.8200.00000129314

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000670.000062rare
Latino/Admixed American0.000380.00038rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000210.00019rare
South Asian0.000160.00016rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid. {ECO:0000269|PubMed:7744740}.;
Disease
DISEASE: Spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME) [MIM:159950]: An autosomal recessive neuromuscular disorder characterized by childhood onset of motor deficits and progressive myoclonic seizures, after normal developmental milestones. Proximal muscle weakness and generalized muscular atrophy are due to degeneration of spinal motor neurons. Myoclonic epilepsy is generally resistant to conventional therapy. The disease course is progressive and leads to respiratory muscle involvement and severe handicap or early death from respiratory insufficiency. {ECO:0000269|PubMed:22703880, ECO:0000269|PubMed:24164096}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.289

Intolerance Scores

LoFtool
0.421
RVIS EVS
0.51
RVIS percentile EVS
80.31

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.973

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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