rs1554032216
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.160G>A(p.Asp54Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000726 in 1,377,616 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. D54A) 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.160G>A | p.Asp54Asn | missense_variant | 1/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.160G>A | p.Asp54Asn | missense_variant | 1/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.160G>A | p.Asp54Asn | missense_variant | 2/8 | 1 | |||
ARSB | ENST00000565165.2 | c.160G>A | p.Asp54Asn | missense_variant | 1/5 | 1 | |||
ARSB | ENST00000521117.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 7.26e-7 AC: 1AN: 1377616Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1AN XY: 682874
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:2
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); Located in a well-established functional domain (PM1); Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 54 of the ARSB protein (p.Asp54Asn). 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: 17458871, 24243352, 26609033). ClinVar contains an entry for this variant (Variation ID: 559730). 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: 27826022). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at