rs765905826
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong
The NM_000487.6(ARSA):βc.1223_1231delβ(p.Ser408_Thr410del) variant causes a 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 (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000028 ( 0 hom. )
Consequence
ARSA
NM_000487.6 inframe_deletion
NM_000487.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.29
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 14 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000487.6
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000487.6.
PP5
?
Variant 22-50625443-GTGGTATCAC-G is Pathogenic according to our data. Variant chr22-50625443-GTGGTATCAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625443-GTGGTATCAC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.1223_1231del | p.Ser408_Thr410del | inframe_deletion | 8/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.1223_1231del | p.Ser408_Thr410del | inframe_deletion | 8/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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?
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32
GnomAD3 exomes AF: 0.00000837 AC: 2AN: 238866Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 129730
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GnomAD4 exome AF: 0.00000276 AC: 4AN: 1447764Hom.: 0 AF XY: 0.00000418 AC XY: 3AN XY: 718444
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Feb 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2020 | 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. - |
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at