rs367543005
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000048.4(ASL):c.1060C>T(p.Gln354Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000048.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.1060C>T | p.Gln354Ter | stop_gained, splice_region_variant | 14/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.1060C>T | p.Gln354Ter | stop_gained, splice_region_variant | 13/16 | ||
ASL | NM_001024944.2 | c.1000C>T | p.Gln334Ter | stop_gained, splice_region_variant | 12/15 | ||
ASL | NM_001024946.2 | c.982C>T | p.Gln328Ter | stop_gained, splice_region_variant | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.1060C>T | p.Gln354Ter | stop_gained, splice_region_variant | 14/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 06, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 05, 2016 | Variant summary: The c.1060C>T variant results in a premature termination codon, predicted to cause a truncated or absent ASL protein, which is a commonly known mechanism for disease. One in-silico tool predicts damaging outcome for this variant. 4/5 splice prediction tools predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies.This variant is not found in 116646 control chromosomes. This variant has been reported in many affected individuals as a founder mutation in the Saudi population (Al-Sayed_JIMD_2005). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 24, 2023 | This sequence change creates a premature translational stop signal (p.Gln354*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with argininosuccinic aciduria (PMID: 16435180). ClinVar contains an entry for this variant (Variation ID: 21253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 14, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2016 | p.Q354* CAG>TAG c.1060C>T nonsense variant in the ASL gene was identified in the homozygous state in 14 of 28 patients from Saudi Arabia who were diagnosed with argininosuccinic aciduria (ASA) after being detected on MS/MS newborn screening (Al-Sayed et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 02, 2016 | - - |
ASL-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2024 | The ASL c.1060C>T variant is predicted to result in premature protein termination (p.Gln354*). This variant was reported to be causative for argininosuccinic aciduria (Al-Sayed et al. 2005. PubMed ID: 16435180; AlTassan et al. 2018. PubMed ID: 29326055). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ASL are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at