rs1299207831
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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.262C>T(p.Gln88Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,525,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.3e-7 ( 0 hom. )
Consequence
ARSB
NM_000046.5 stop_gained
NM_000046.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.42
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 5-78984987-G-A is Pathogenic according to our data. Variant chr5-78984987-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 559752.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.262C>T | p.Gln88Ter | stop_gained | 1/8 | ENST00000264914.10 | NP_000037.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.262C>T | p.Gln88Ter | stop_gained | 1/8 | 1 | NM_000046.5 | ENSP00000264914 | P1 | |
ARSB | ENST00000396151.7 | c.262C>T | p.Gln88Ter | stop_gained | 2/8 | 1 | ENSP00000379455 | |||
ARSB | ENST00000565165.2 | c.262C>T | p.Gln88Ter | stop_gained | 1/5 | 1 | ENSP00000456339 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151830Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 7.28e-7 AC: 1AN: 1373898Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1AN XY: 682636
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GnomAD4 genome AF: 0.00000659 AC: 1AN: 151830Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74164
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | Nonsense variant (PVS1); Absent from Gnomad (PM2); Reputable source identifies as pathogenic (PP5) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 25, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 559752). This premature translational stop signal has been observed in individual(s) with ARSB-related conditions (PMID: 24875751). This sequence change creates a premature translational stop signal (p.Gln88*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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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