rs752100894
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000048.4(ASL):āc.260A>Gā(p.Asp87Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,796 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 ). Synonymous variant affecting the same amino acid position (i.e. D87D) has been classified as Likely benign.
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.260A>G | p.Asp87Gly | missense_variant | 4/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.260A>G | p.Asp87Gly | missense_variant | 3/16 | ||
ASL | NM_001024944.2 | c.260A>G | p.Asp87Gly | missense_variant | 3/15 | ||
ASL | NM_001024946.2 | c.260A>G | p.Asp87Gly | missense_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.260A>G | p.Asp87Gly | missense_variant | 4/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000812 AC: 2AN: 246284Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133324
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459796Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 725988
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 31, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 87 of the ASL protein (p.Asp87Gly). 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: 12384776, 24166829). ClinVar contains an entry for this variant (Variation ID: 557253). 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: 11747433). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at