7-66086764-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000304874.14(ASL):c.545G>A(p.Arg182Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,603,044 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. R182G) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000304874.14 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.545G>A | p.Arg182Gln | missense_variant | 8/17 | ENST00000304874.14 | NP_000039.2 | |
ASL | NM_001024943.2 | c.545G>A | p.Arg182Gln | missense_variant | 7/16 | NP_001020114.1 | ||
ASL | NM_001024944.2 | c.545G>A | p.Arg182Gln | missense_variant | 7/15 | NP_001020115.1 | ||
ASL | NM_001024946.2 | c.524+102G>A | intron_variant | NP_001020117.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.545G>A | p.Arg182Gln | missense_variant | 8/17 | 1 | NM_000048.4 | ENSP00000307188 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000220 AC: 5AN: 227286Hom.: 0 AF XY: 0.0000405 AC XY: 5AN XY: 123504
GnomAD4 exome AF: 0.0000365 AC: 53AN: 1450900Hom.: 0 Cov.: 32 AF XY: 0.0000444 AC XY: 32AN XY: 721112
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 04, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 16, 2023 | PS3, PM3, PM2, PM1, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the ASL protein (p.Arg182Gln). This variant is present in population databases (rs751590073, gnomAD 0.005%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 19703900, 24166829; Invitae; RQ355872). 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: 203613). 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%. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Dec 04, 2015 | The c.545G>A (p.Arg182Gln) missense variant in the ASL gene has been previously reported in one affected individual with autosomal recessive Argininosuccinic aciduria. The affected individual harbored this missense variant in trans with a canonical splice site variant (IVS5+1G>A) reported to cause a premature protein truncation (Linnebank et al., 2002). Cultured fibroblast from this individual showed the enzyme activity of ASL was less than 2% relative to controls (Linnebank et al., 2002). The c.545G>A variant is located within a mutational hotspot which includes exons 5, 6, and 8 (Linnebank et al., 2002). Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009). The c.545G>A variant has been reported at low frequencies in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and multiple lines of computation evidence suggest a deleterious effect (GERP = 5.65; CADD = 34; polyPhen = 0.997; SIFT = 0). In addition, this variant has been reported as pathogenic in ClinVar by another clinical laboratory. Therefore, this collective evidence supports the classification of the c.545G>A (p.Arg182Gln) as a recessive Pathogenic variant for Argininosuccinic aciduria. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at