chr7-66082441-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000048.4(ASL):c.281G>A(p.Arg94His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,609,724 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000048.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.281G>A | p.Arg94His | missense_variant | 4/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.281G>A | p.Arg94His | missense_variant | 3/16 | ||
ASL | NM_001024944.2 | c.281G>A | p.Arg94His | missense_variant | 3/15 | ||
ASL | NM_001024946.2 | c.281G>A | p.Arg94His | missense_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.281G>A | p.Arg94His | missense_variant | 4/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457598Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2AN XY: 724692
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 15, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the ASL protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829). ClinVar contains an entry for this variant (Variation ID: 550701). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg94 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24166829, 26745957; Invitae). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2019 | In a cohort of individuals reported to have ASL deficiency, R94H reported in an individual in whom a second variant was identified, however clinical and biochemical information was not provided (Balmer et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24166829) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at