rs759384989
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.936G>T(p.Trp312Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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.936G>T | p.Trp312Cys | 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.936G>T | p.Trp312Cys | missense_variant | Exon 5 of 8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.936G>T | p.Trp312Cys | missense_variant | Exon 6 of 8 | 1 | ENSP00000379455.3 | |||
ARSB | ENST00000565165.2 | c.936G>T | p.Trp312Cys | missense_variant | Exon 5 of 5 | 1 | ENSP00000456339.2 | |||
ARSB | ENST00000521800.2 | n.118G>T | non_coding_transcript_exon_variant | Exon 2 of 3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:5
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000549491). A different missense change at the same codon (p.Trp312Arg) has been reported to be associated with ARSB-related disorder (PMID: 17458871). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Experimental studies have shown that this missense change affects ARSB function (PMID: 14974081). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 312 of the ARSB protein (p.Trp312Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 14974081). ClinVar contains an entry for this variant (Variation ID: 549491). -
This variant is interpreted as a Likely Pathogenic, for Mucopolysaccharidosis type VI, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:14974081). -
- -
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at