rs1554086435
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000046.5(ARSB):c.710C>A(p.Ala237Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000046.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.710C>A | p.Ala237Asp | missense_variant | Exon 4 of 8 | ENST00000264914.10 | NP_000037.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.710C>A | p.Ala237Asp | missense_variant | Exon 4 of 8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.710C>A | p.Ala237Asp | missense_variant | Exon 5 of 8 | 1 | ENSP00000379455.3 | |||
ARSB | ENST00000565165.2 | c.710C>A | p.Ala237Asp | missense_variant | Exon 4 of 5 | 1 | ENSP00000456339.2 | |||
ARSB | ENST00000521800.2 | n.-109C>A | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:1Benign:1
Variant summary: ARSB c.710C>A (p.Ala237Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251326 control chromosomes (gnomAD). c.710C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome; e.g. Brands_2013, Uttarilli_2017). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Brands_2013, Uttarilli_2017). The following publications have been ascertained in the context of this evaluation (PMID: 23557332, 27826022). ClinVar contains an entry for this variant (Variation ID: 559805). Based on the evidence outlined above, the variant was classified as pathogenic. -
In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at