7-66083105-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000048.4(ASL):c.377G>A(p.Arg126Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,774 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R126W) 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.377G>A | p.Arg126Gln | missense_variant | 6/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.377G>A | p.Arg126Gln | missense_variant | 5/16 | ||
ASL | NM_001024944.2 | c.377G>A | p.Arg126Gln | missense_variant | 5/15 | ||
ASL | NM_001024946.2 | c.377G>A | p.Arg126Gln | missense_variant | 5/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.377G>A | p.Arg126Gln | missense_variant | 6/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000799 AC: 2AN: 250468Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135638
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461546Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727068
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74426
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Feb 05, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 18, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 126 of the ASL protein (p.Arg126Gln). This variant is present in population databases (rs777235530, gnomAD 0.004%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 28251416; Invitae). ClinVar contains an entry for this variant (Variation ID: 556429). 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.Arg126 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 20236848, 24166829), which suggests that this may be a clinically significant amino acid residue. 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