rs746120802
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000048.4(ASL):c.1154G>A(p.Arg385His) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,457,082 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. R385L) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.1154G>A | p.Arg385His | missense_variant | 16/17 | ENST00000304874.14 | NP_000039.2 | |
ASL | NM_001024943.2 | c.1154G>A | p.Arg385His | missense_variant | 15/16 | NP_001020114.1 | ||
ASL | NM_001024944.2 | c.1094G>A | p.Arg365His | missense_variant | 14/15 | NP_001020115.1 | ||
ASL | NM_001024946.2 | c.1076G>A | p.Arg359His | missense_variant | 14/15 | NP_001020117.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.1154G>A | p.Arg385His | missense_variant | 16/17 | 1 | NM_000048.4 | ENSP00000307188.9 | ||
ENSG00000249319 | ENST00000450043.2 | c.467G>A | p.Arg156His | missense_variant | 7/12 | 5 | ENSP00000396527.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247896Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134470
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1457082Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 725024
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:5Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 28, 2023 | This variant is present in population databases (rs746120802, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg385 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12408190, 18616627, 21667091, 25778938, 26745957). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 552287). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 24166829, 31943503; Invitae). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 385 of the ASL protein (p.Arg385His). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 15, 2023 | Criteria applied: PS3_MOD,PM3,PM5,PP4_MOD,PM2_SUP,PP3 - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Jun 02, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2023 | Variant summary: ASL c.1154G>A (p.Arg385His) results in a non-conservative amino acid change located in the Argininosuccinate lyase, C-terminal domain (IPR029419) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247896 control chromosomes (gnomAD). c.1154G>A has been reported in the literature in individuals affected with Argininosuccinic Aciduria (example: Balmer_2014 and Zielonka_2020). These data indicate that the variant may be associated with disease. A different amino acid change affecting the same residue (c.1154G>T/p.Arg385Leu) has been reported in individuals affected with Argininosuccinic Aciduria in homozygous state (Balmer_2014). This data suggests that this residue is critical for normal protein function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 02, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at