rs755635209
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000216124.10(ARSA):βc.1264delβ(p.Leu422Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000313 in 1,597,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
ARSA
ENST00000216124.10 frameshift
ENST00000216124.10 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.28
Genes affected
ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-50625410-AG-A is Pathogenic according to our data. Variant chr22-50625410-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.1264del | p.Leu422Ter | frameshift_variant | 8/8 | ENST00000216124.10 | NP_000478.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.1264del | p.Leu422Ter | frameshift_variant | 8/8 | 1 | NM_000487.6 | ENSP00000216124 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000417 AC: 1AN: 239782Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129862
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1444900Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1AN XY: 716380
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 15, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ARSA protein in which other variant(s) (p.Pro428Leu) have been determined to be pathogenic (PMID: 1670590, 9090526, 9096767, 11941485, 26462614). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 424522). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. This variant is present in population databases (rs755635209, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Leu422*) in the ARSA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the ARSA protein. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 22, 2018 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2023 | Has not been previously published as pathogenic or benign to our knowledge; Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at