rs869312985
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000048.4(ASL):c.175G>A(p.Glu59Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,224 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E59V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000048.4 missense
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 |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.175G>A | p.Glu59Lys | missense_variant | 3/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.175G>A | p.Glu59Lys | missense_variant | 2/16 | ||
ASL | NM_001024944.2 | c.175G>A | p.Glu59Lys | missense_variant | 2/15 | ||
ASL | NM_001024946.2 | c.175G>A | p.Glu59Lys | missense_variant | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.175G>A | p.Glu59Lys | missense_variant | 3/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460224Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726288
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 01, 2022 | For these reasons, this variant has been classified as Pathogenic. 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 ASL protein function. ClinVar contains an entry for this variant (Variation ID: 224970). This missense change has been observed in individual(s) with ASL deficiency (PMID: 12384776; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 59 of the ASL protein (p.Glu59Lys). - |
Pathogenic, criteria provided, single submitter | literature only | SNPedia | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 19, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12384776, 31589614) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at