NM_000046.5:c.275C>A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.275C>A(p.Thr92Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,924 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
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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.275C>A | p.Thr92Lys | missense_variant | Exon 1 of 8 | ENST00000264914.10 | NP_000037.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.275C>A | p.Thr92Lys | missense_variant | Exon 1 of 8 | 1 | NM_000046.5 | ENSP00000264914.4 | ||
ARSB | ENST00000396151.7 | c.275C>A | p.Thr92Lys | missense_variant | Exon 2 of 8 | 1 | ENSP00000379455.3 | |||
ARSB | ENST00000565165.2 | c.275C>A | p.Thr92Lys | missense_variant | Exon 1 of 5 | 1 | ENSP00000456339.2 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151816Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1360288Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 675310
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151924Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74262
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:2Uncertain:1
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Absent from GnomAD (PM2); Reputable source identifies as pathogenic (PP5) -
This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871, 30982216). ClinVar contains an entry for this variant (Variation ID: 559758). 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 variant disrupts the p.Thr92 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been observed in individuals with ARSB-related conditions (PMID: 8651289, 29202552), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 92 of the ARSB protein (p.Thr92Lys). -
ARSB-related disorder Pathogenic:1
The ARSB c.275C>A variant is predicted to result in the amino acid substitution p.Thr92Lys. This variant was reported in the compound heterozygous and homozygous state in several unrelated individuals with mucopolysaccharidosis VI (Supp. Table 1 in Karageorgos et al 2007. PubMed ID: 17458871; Jafaryazdi R et al 2019. PubMed ID: 30982216). Other amino acid substitutions at this position (p.Thr92Met, p.Thr92Pro) have also been reported in patients with mucopolysaccharidosis VI (Litjens et al 1996. PubMed ID: 8651289; Abbasi et al 2017. PubMed ID: 29202552). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at