5-78984965-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.284G>A(p.Arg95Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000537 in 1,488,434 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. R95L) 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.284G>A | p.Arg95Gln | missense_variant | 1/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.284G>A | p.Arg95Gln | missense_variant | 1/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.284G>A | p.Arg95Gln | missense_variant | 2/8 | 1 | |||
ARSB | ENST00000565165.2 | c.284G>A | p.Arg95Gln | missense_variant | 1/5 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151696Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000678 AC: 1AN: 147456Hom.: 0 AF XY: 0.0000119 AC XY: 1AN XY: 84196
GnomAD4 exome AF: 0.00000524 AC: 7AN: 1336738Hom.: 0 Cov.: 31 AF XY: 0.00000755 AC XY: 5AN XY: 662560
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151696Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74062
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 95 of the ARSB protein (p.Arg95Gln). This variant is present in population databases (rs118203942, gnomAD 0.001%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 8651289; Invitae). ClinVar contains an entry for this variant (Variation ID: 884). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSB function (PMID: 8651289). For these reasons, this variant has been classified as Pathogenic. - |
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 ExAc (PM2); Reputable source identifies as pathogenic (PP5) - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at