rs750845916
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000046.5(ARSB):c.245delT(p.Leu82fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000577 in 1,387,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000058 ( 0 hom. )
Consequence
ARSB
NM_000046.5 frameshift
NM_000046.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.03
Genes affected
ARSB (HGNC:714): (arylsulfatase B) Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-78985003-CA-C is Pathogenic according to our data. Variant chr5-78985003-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.245delT | p.Leu82fs | frameshift_variant | 1/8 | ENST00000264914.10 | NP_000037.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.245delT | p.Leu82fs | frameshift_variant | 1/8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.245delT | p.Leu82fs | frameshift_variant | 2/8 | 1 | ENSP00000379455.3 | |||
ARSB | ENST00000565165.2 | c.245delT | p.Leu82fs | frameshift_variant | 1/5 | 1 | ENSP00000456339.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000567 AC: 1AN: 176244Hom.: 0 AF XY: 0.0000100 AC XY: 1AN XY: 99946
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GnomAD4 exome AF: 0.00000577 AC: 8AN: 1387590Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5AN XY: 689762
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 07, 2022 | This sequence change creates a premature translational stop signal (p.Leu82Argfs*32) in the ARSB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSB are known to be pathogenic (PMID: 17458871, 22133300). This variant is present in population databases (rs750845916, gnomAD 0.001%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 559746). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 10923267). - |
Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | Frameshift variant (PVS1); Very low frequence in GnomAd (PM2) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at