rs768012515
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5
The NM_000046.5(ARSB):c.1336+2T>G variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000046.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.1336+2T>G | splice_donor_variant | ENST00000264914.10 | |||
ARSB | XM_011543390.2 | c.1336+2T>G | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.1336+2T>G | splice_donor_variant | 1 | NM_000046.5 | P1 | |||
ARSB | ENST00000521011.1 | n.301+2T>G | splice_donor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251398Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727186
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | Splicing variant in canonical site (PVS1); In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change affects a donor splice site in intron 7 of the ARSB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs768012515, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 14974081, 17458871, 24875751). ClinVar contains an entry for this variant (Variation ID: 559702). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 29, 2022 | Variant summary: ARSB c.1336+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251398 control chromosomes (gnomAD). c.1336+2T>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome), including two homozygotes (Karageorgos_2004, Karageorgos_2007, Chistiakov_2014). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at