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GeneBe

ARSA

arylsulfatase A, the group of Sulfatases

Basic information

Region (hg38): 22:50622753-50628173

Links

ENSG00000100299 ∙ NCBI:410 ∙ OMIM:607574 ∙ HGNC:713 ∙ Uniprot:P15289 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • metachromatic leukodystrophy (Definitive), mode of inheritance: AR
  • metachromatic leukodystrophy, juvenile form (Definitive), mode of inheritance: AR
  • metachromatic leukodystrophy, juvenile form (Strong), mode of inheritance: AR
  • metachromatic leukodystrophy, juvenile form (Definitive), mode of inheritance: AR
  • metachromatic leukodystrophy, juvenile form (Strong), mode of inheritance: AR
  • metachromatic leukodystrophy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Metachromatic leukodystrophyARGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingBiochemical; Neurologic21611375; 5828490; 14206875; 5642751; 5751920; 5367045; 4192207; 2863494; 2876627; 3813937; 1676699; 1678251; 1684088; 1673113; 1673291; 1670590; 15710861; 16966551; 18786133; 19067349; 23845948
BMT, as well as gene therapy, has been described

ClinVar

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

  • Metachromatic leukodystrophy (937 variants)
  • not provided (191 variants)
  • not specified (34 variants)
  • Inborn genetic diseases (29 variants)
  • Metachromatic leukodystrophy, severe (8 variants)
  • Metachromatic leukodystrophy, adult type (6 variants)
  • Metachromatic leukodystrophy, juvenile type (6 variants)
  • Metachromatic leukodystrophy, late infantile form (5 variants)
  • Intellectual disability (3 variants)
  • ARSA-related condition (3 variants)
  • Neurodevelopmental disorder (2 variants)
  • Arylsulfatase A pseudodeficiency (2 variants)
  • Metachromatic leukodystrophy, mild (2 variants)
  • Citrullinemia (2 variants)
  • Metachromatic leukodystrophy, late-onset (1 variants)
  • Arylsulfatase a, allele a (1 variants)
  • See cases (1 variants)
  • Spastic ataxia (1 variants)
  • Abnormality of the nervous system (1 variants)
  • Autosomal recessive sideroblastic anemia (1 variants)
  • ARYLSULFATASE A POLYMORPHISM (1 variants)
  • Pseudoarylsulfatase A deficiency (1 variants)
  • Leukodystrophy (1 variants)
  • Arylsulfatase a pseudodeficiency, intermediate (1 variants)
  • Arylsulfatase a pseudodeficiency, severe (1 variants)
  • Frontotemporal dementia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARSA 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
clinvar
6
clinvar
227
clinvar
6
clinvar
 240
missense
37
clinvar
83
clinvar
203
clinvar
7
clinvar
4
clinvar
 334
nonsense
17
clinvar
7
clinvar
 24
start loss
1
clinvar
 1
frameshift
39
clinvar
38
clinvar
1
clinvar
 78
inframe indel
4
clinvar
1
clinvar
4
clinvar
 9
splice donor/acceptor (+/-2bp)
13
clinvar
12
clinvar
2
clinvar
 27
splice region
?
    Intron variants in splice region, excluding donor/acceptor (+/-2bp)
17
24
1
 42
non coding
?
    UTR, intron and other, non coding variants
76
clinvar
66
clinvar
30
clinvar
 172
Total 110 143 292 300 40

Highest pathogenic variant AF is 0.000427

Variants in ARSA

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

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

Position Type Phenotype Significance ClinVar
22-50622771-G-T Metachromatic leukodystrophy Likely benign (Jan 13, 2018)342183
22-50622777-T-A Metachromatic leukodystrophy Uncertain significance (Jan 17, 2018)899550
22-50622829-G-A Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)342184
22-50622844-A-G Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)342185
22-50622862-T-C Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)899551
22-50622886-C-T Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)342186
22-50622940-T-A Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)342187
22-50623011-G-T Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)899552
22-50623051-AAGG-A Metachromatic leukodystrophy Uncertain significance (Jun 14, 2016)342188
22-50623080-G-A Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)900690
22-50623108-G-A Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)900691
22-50623122-C-G Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)342189
22-50623158-C-T Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)342190
22-50623176-G-T Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)900692
22-50623320-G-A Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)900693
22-50623376-T-C Metachromatic leukodystrophy Benign (Jan 12, 2018)342191
22-50623399-C-T Metachromatic leukodystrophy Benign (Jan 13, 2018)342192
22-50623431-C-T Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)902371
22-50623433-G-A Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)902372
22-50623516-T-G Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)342193
22-50623518-C-G Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)342194
22-50623528-C-T Metachromatic leukodystrophy Uncertain significance (Jan 12, 2018)342195
22-50623569-T-G Metachromatic leukodystrophy Uncertain significance (Jan 13, 2018)342196
22-50623575-G-A Metachromatic leukodystrophy Benign (Jan 13, 2018)342197
22-50623623-G-T Metachromatic leukodystrophy Benign (Jan 13, 2018)342198

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
ARSAprotein_codingprotein_codingENST00000216124 85426
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
1.09e-110.088012551102181257290.000867
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense0.3802983170.9400.00002003185
Missense in Polyphen124133.610.928071359
Synonymous-0.1641461441.020.000009451151
Loss of Function0.3991819.90.9030.00000130185

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.001160.00112
Ashkenazi Jewish0.00009940.0000992
East Asian0.0003440.000326
Finnish0.0004820.000462
European (Non-Finnish)0.001480.00139
Middle Eastern0.0003440.000326
South Asian0.0002690.000261
Other0.001550.00147

dbNSFP

Source: dbNSFP

Function
FUNCTION: Hydrolyzes cerebroside sulfate. {ECO:0000269|PubMed:10751093}.;
Disease
DISEASE: Metachromatic leukodystrophy (MLD) [MIM:250100]: An autosomal recessive disease caused by abnormal intralysosomal accumulation of cerebroside-3-sulfate in central and peripheral nervous systems, as well as other organs. MLD is clinically characterized by leukodystrophy, progressive demyelination and a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Decreased arylsulfatase A activity is detected in urine, leukocytes, and fibroblasts of affected individuals. Several forms of the disease can be distinguished according to the age at onset and disease severity: late infantile, juvenile and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency. Individuals with pseudoarylsulfatase A deficiency have low arylsulfatase A activity but lack neurological manifestations and are apparently healthy. {ECO:0000269|PubMed:10220151, ECO:0000269|PubMed:10381328, ECO:0000269|PubMed:10477432, ECO:0000269|PubMed:10533072, ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:11020646, ECO:0000269|PubMed:11061266, ECO:0000269|PubMed:11456299, ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:12503099, ECO:0000269|PubMed:12788103, ECO:0000269|PubMed:1353340, ECO:0000269|PubMed:14517960, ECO:0000269|PubMed:14680985, ECO:0000269|PubMed:15026521, ECO:0000269|PubMed:15326627, ECO:0000269|PubMed:15710861, ECO:0000269|PubMed:1670590, ECO:0000269|PubMed:1673291, ECO:0000269|PubMed:1678251, ECO:0000269|PubMed:18693274, ECO:0000269|PubMed:19606494, ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:21265945, ECO:0000269|PubMed:2574462, ECO:0000269|PubMed:7581401, ECO:0000269|PubMed:7825603, ECO:0000269|PubMed:7860068, ECO:0000269|PubMed:7902317, ECO:0000269|PubMed:7906588, ECO:0000269|PubMed:7909527, ECO:0000269|PubMed:8095918, ECO:0000269|PubMed:8101038, ECO:0000269|PubMed:8101083, ECO:0000269|PubMed:8104633, ECO:0000269|PubMed:8891236, ECO:0000269|PubMed:9090526, ECO:0000269|PubMed:9272717, ECO:0000269|PubMed:9452102, ECO:0000269|PubMed:9490297, ECO:0000269|PubMed:9600244, ECO:0000269|PubMed:9819708}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple sulfatase deficiency (MSD) [MIM:272200]: A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post- translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. {ECO:0000269|PubMed:15146462}. Note=The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1 (PubMed:15146462). SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3- oxoalanine (PubMed:7628016). {ECO:0000269|PubMed:15146462, ECO:0000269|PubMed:7628016}.;
Pathway
Lysosome - Homo sapiens (human);Sphingolipid metabolism - Homo sapiens (human);Sphingolipid Metabolism;Gaucher Disease;Globoid Cell Leukodystrophy;Metachromatic Leukodystrophy (MLD);Fabry disease;Krabbe disease;Degradation pathway of sphingolipids, including diseases;Neutrophil degranulation;Metabolism of lipids;Post-translational protein modification;Metabolism of proteins;The activation of arylsulfatases;Gamma carboxylation, hypusine formation and arylsulfatase activation;Innate Immune System;Immune System;Metabolism;Glycosphingolipid metabolism;Sphingolipid metabolism (Consensus)

Recessive Scores

pRec
0.698

Intolerance Scores

loftool
0.00558
rvis_EVS
0.16
rvis_percentile_EVS
64.82

Haploinsufficiency Scores

pHI
0.153
hipred
N
hipred_score
0.197
ghis
0.483

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
N
gene_indispensability_score
0.153

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Arsa
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; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; homeostasis/metabolism phenotype;

Zebrafish Information Network

Gene name
arsa
Affected structure
macrophage
Phenotype tag
abnormal
Phenotype quality
morphology

Gene ontology

Biological process
glycosphingolipid metabolic process;neutrophil degranulation
Cellular component
extracellular region;lysosome;endoplasmic reticulum lumen;azurophil granule lumen;lysosomal lumen;extracellular exosome
Molecular function
arylsulfatase activity;cerebroside-sulfatase activity;calcium ion binding;protein binding;sulfuric ester hydrolase activity