rs143508372
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000048.4(ASL):āc.571C>Gā(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,498 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191W) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.571C>G | p.Arg191Gly | missense_variant | 8/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.571C>G | p.Arg191Gly | missense_variant | 7/16 | ||
ASL | NM_001024944.2 | c.571C>G | p.Arg191Gly | missense_variant | 7/15 | ||
ASL | NM_001024946.2 | c.524+128C>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.571C>G | p.Arg191Gly | missense_variant | 8/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000482 AC: 1AN: 207286Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 112280
GnomAD4 exome AF: 0.00000209 AC: 3AN: 1438498Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2AN XY: 713754
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:2Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 17, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 191 of the ASL protein (p.Arg191Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ASL-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 692055). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASL protein function. This variant disrupts the p.Arg191 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21744316, 24166829, 31943503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Oct 12, 2018 | This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a variant involving the same amino acid but resulting in a different missense change (p.Arg191Trp) has been previously reported in an asymptomatic patient with argininosuccinate lyase deficiency detected by newborn screening (PMID: 24166829). The c.571C>G (p.Arg191Gly) variant detected in this individual is present in the heterozygous state in the gnomAD population database at a frequency of 0.0005% (1/201720) and thus is presumed to be rare. Based on the available evidence, the c.571C>G p.Arg191Gly variant is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at