rs74315464
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The ENST00000216124.10(ARSA):c.470C>T(p.Pro157Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,604,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157R) has been classified as Pathogenic.
Frequency
Consequence
ENST00000216124.10 missense
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.470C>T | p.Pro157Leu | missense_variant | 3/8 | ENST00000216124.10 | NP_000478.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.470C>T | p.Pro157Leu | missense_variant | 3/8 | 1 | NM_000487.6 | ENSP00000216124 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000758 AC: 11AN: 1451980Hom.: 0 Cov.: 33 AF XY: 0.00000832 AC XY: 6AN XY: 720750
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 28, 2021 | PP4, PM2, PM3 - |
Metachromatic leukodystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 15, 2018 | The ARSA c.470C>T (p.Pro157Leu) variant is a missense variant that has been reported in a compound heterozygous state in one individual with juvenile arylsulfatase A deficiency (Eng et al. 2003). The p.Pro157Leu variant was not found in 50 control individuals but is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Pro157Leu variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for arylsulfatase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 12, 2021 | This sequence change replaces proline with leucine at codon 157 of the ARSA protein (p.Pro157Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 14517960). This variant is also known as P155L. ClinVar contains an entry for this variant (Variation ID: 68137). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at