rs1554069775
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000046.5(ARSB):c.1334C>T(p.Pro445Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000046.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.1334C>T | p.Pro445Leu | missense_variant, splice_region_variant | 7/8 | ENST00000264914.10 | |
ARSB | XM_011543390.2 | c.1334C>T | p.Pro445Leu | missense_variant, splice_region_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.1334C>T | p.Pro445Leu | missense_variant, splice_region_variant | 7/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000521011.1 | n.299C>T | splice_region_variant, non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727186
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2019 | This sequence change replaces proline with leucine at codon 445 of the ARSB protein (p.Pro445Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous in an individual affected with mucopolysaccharidosis type VI but it co-occurs with another homozygous ARSB variant in cis (PMID: 24677745). ClinVar contains an entry for this variant (Variation ID: 559701). Experimental studies have shown that this missense change abrogates ARSB enzyme activity (PMID: 27826022). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | 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