rs786204748
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong
The NM_000487.6(ARSA):c.1223_1231delGTGATACCA(p.Ser408_Thr410del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000276 in 1,447,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000487.6 disruptive_inframe_deletion
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 |
---|---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.1223_1231delGTGATACCA | p.Ser408_Thr410del | disruptive_inframe_deletion | Exon 8 of 8 | ENST00000216124.10 | NP_000478.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.1223_1231delGTGATACCA | p.Ser408_Thr410del | disruptive_inframe_deletion | Exon 8 of 8 | 1 | NM_000487.6 | ENSP00000216124.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000837 AC: 2AN: 238866Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 129730
GnomAD4 exome AF: 0.00000276 AC: 4AN: 1447764Hom.: 0 AF XY: 0.00000418 AC XY: 3AN XY: 718444
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:4Other:1
This variant, c.1223_1231del, results in the deletion of 3 amino acid(s) of the ARSA protein (p.Ser408_Thr410del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765905826, gnomAD 0.003%). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9490297, 12809637, 18786133, 22993277, 23559313). This variant is also known as c.1215_1223del, c.1216-24del9, c.1216del9, c.1217_1225del, and 2320del9. ClinVar contains an entry for this variant (Variation ID: 189170). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: ARSA c.1223_1231delGTGATACCA (p.Ser408_Thr410del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 8.4e-06 in 238866 control chromosomes. c.1223_1231delGTGATACCA has been reported in the literature in multiple individuals affected with Metachromatic Leukodystrophy (Regis_1998, Biffi_2008, Cesani_2015, Rafi_2003, Galla_2013). These data indicate that the variant is very likely to be associated with disease. The variant results in significantly reduced enzyme activity (Regis_1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at