rs869312994
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000048.4(ASL):c.1360C>T(p.Gln454Ter) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ASL
NM_000048.4 stop_gained
NM_000048.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.43
Genes affected
ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-66092877-C-T is Pathogenic according to our data. Variant chr7-66092877-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66092877-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.1360C>T | p.Gln454Ter | stop_gained | 17/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.1360C>T | p.Gln454Ter | stop_gained | 16/16 | ||
ASL | NM_001024944.2 | c.1300C>T | p.Gln434Ter | stop_gained | 15/15 | ||
ASL | NM_001024946.2 | c.1282C>T | p.Gln428Ter | stop_gained | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.1360C>T | p.Gln454Ter | stop_gained | 17/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2022 | Variant summary: ASL c.1360C>T (p.Gln454X) results in a premature termination codon, expected to cause a truncation of the encoded protein (removing the last 11 amino acids), which is a commonly known mechanism for disease. A truncation downstream of this position (c.1378C>T, p.Gln460X) has been reported in a severely affected patient (PMID: 24166829). The variant was absent in 247240 control chromosomes (gnomAD). c.1360C>T has been reported in the literature in an individual affected with Argininosuccinic Aciduria (Barbosa_1991). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | literature only | SNPedia | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at