rs752783461
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000048.4(ASL):c.338G>A(p.Arg113Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,476 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. R113W) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.338G>A | p.Arg113Gln | missense_variant | 5/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.338G>A | p.Arg113Gln | missense_variant | 4/16 | ||
ASL | NM_001024944.2 | c.338G>A | p.Arg113Gln | missense_variant | 4/15 | ||
ASL | NM_001024946.2 | c.338G>A | p.Arg113Gln | missense_variant | 4/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.338G>A | p.Arg113Gln | missense_variant | 5/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249850Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135402
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461414Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 726990
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74270
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 29, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 113 of the ASL protein (p.Arg113Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 17326097). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555191). 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. Experimental studies have shown that this missense change affects ASL function (PMID: 31943503). This variant disrupts the p.Arg113 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10896281, 24166829). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at