rs398123414
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000487.6(ARSA):c.195del(p.Tyr65Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,410,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y65Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000487.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSA | NM_000487.6 | c.195del | p.Tyr65Ter | frameshift_variant | 1/8 | ENST00000216124.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSA | ENST00000216124.10 | c.195del | p.Tyr65Ter | frameshift_variant | 1/8 | 1 | NM_000487.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000586 AC: 1AN: 170516Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 90922
GnomAD4 exome AF: 0.00000213 AC: 3AN: 1410300Hom.: 0 Cov.: 33 AF XY: 0.00000430 AC XY: 3AN XY: 696868
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Metachromatic leukodystrophy Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 23, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Tyr65*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is present in population databases (rs398123414, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with metachromatic leukodystrophy (PMID: 24001781, 28762252). This variant is also known as 189delC, Y63X. ClinVar contains an entry for this variant (Variation ID: 93121). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Neurometabolisches Labor, University hospital Tuebingen | May 01, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 20, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 10, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at