rs398123125
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.971G>T(p.Gly324Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,010 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 (★★).
Frequency
Consequence
NM_000046.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.971G>T | p.Gly324Val | missense_variant | Exon 5 of 8 | ENST00000264914.10 | NP_000037.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.971G>T | p.Gly324Val | missense_variant | Exon 5 of 8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.971G>T | p.Gly324Val | missense_variant | Exon 6 of 8 | 1 | ENSP00000379455.3 | |||
ARSB | ENST00000565165.2 | c.971G>T | p.Gly324Val | missense_variant | Exon 5 of 5 | 1 | ENSP00000456339.2 | |||
ARSB | ENST00000521800.2 | n.153G>T | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251372Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135854
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:5
In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequencyin GnomAD (PM2); Reputable source identifies as pathogenic (PP5) -
- -
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 324 of the ARSB protein (p.Gly324Val). This variant is present in population databases (rs398123125, gnomAD 0.007%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871, 23557332; Invitae). ClinVar contains an entry for this variant (Variation ID: 92356). 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%. Studies have shown that this missense change alters ARSB gene expression (PMID: 23557332). For these reasons, this variant has been classified as Pathogenic. -
- -
Variant summary: ARSB c.971G>T (p.Gly324Val) results in a non-conservative amino acid change in the Sulfatase, N-terminal domain of the encoded protein sequence. Five 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 251372 control chromosomes. c.971G>T has been reported in the literature in at-least one individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) 9Example: Ebbink_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Brands_2013). The following publications have been ascertained in the context of this evaluation (PMID: 26450354, 17458871, 33209960, 25654180, 23557332). ClinVar contains an entry for this variant (Variation ID: 92356). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Inborn genetic diseases Pathogenic:1
- -
not provided Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at