rs527640350
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000487.6(ARSA):āc.674A>Gā(p.Tyr225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,942 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).
Frequency
Consequence
NM_000487.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.674A>G | p.Tyr225Cys | missense_variant | 3/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.674A>G | p.Tyr225Cys | missense_variant | 3/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151816Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250758Hom.: 0 AF XY: 0.0000885 AC XY: 12AN XY: 135644
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461008Hom.: 0 Cov.: 33 AF XY: 0.0000509 AC XY: 37AN XY: 726684
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 151934Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74238
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:2Uncertain:1Other:1
not provided, no classification provided | in vitro | Gelb Laboratory, University of Washington | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects ARSA function (PMID: 28762252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. ClinVar contains an entry for this variant (Variation ID: 431088). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 28762252). This variant is present in population databases (rs527640350, gnomAD 0.05%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the ARSA protein (p.Tyr225Cys). - |
Pathogenic, criteria provided, single submitter | research | Neurometabolisches Labor, University hospital Tuebingen | May 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at