chr5-78969026-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.479G>A(p.Arg160Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,876 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000046.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.479G>A | p.Arg160Gln | missense_variant | 2/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.479G>A | p.Arg160Gln | missense_variant | 2/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.479G>A | p.Arg160Gln | missense_variant | 3/8 | 1 | |||
ARSB | ENST00000565165.2 | c.479G>A | p.Arg160Gln | missense_variant | 2/5 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251478Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:5
Likely pathogenic, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in GnomAD (PM2) - |
Pathogenic, criteria provided, single submitter | research | Medical Molecular Genetics Department, National Research Center | Dec 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2023 | Variant summary: ARSB c.479G>A (p.Arg160Gln) results in a conservative amino acid change located in the sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes (gnomAD). c.479G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (e.g. Voskoboeva_1994, Garrido_2007, Kantaputra_2014, Fang_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34813777, 17643332, 22133300, 24677745, 8125475). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 24, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function. ClinVar contains an entry for this variant (Variation ID: 445292). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 160 of the ARSB protein (p.Arg160Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 8125475, 17643332, 22133300, 24677745, 27797586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at