rs1554328459
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000048.4(ASL):āc.1297A>Cā(p.Ser433Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,522 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. S433S) 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASL | NM_000048.4 | c.1297A>C | p.Ser433Arg | missense_variant | 17/17 | ENST00000304874.14 | |
ASL | NM_001024943.2 | c.1297A>C | p.Ser433Arg | missense_variant | 16/16 | ||
ASL | NM_001024944.2 | c.1237A>C | p.Ser413Arg | missense_variant | 15/15 | ||
ASL | NM_001024946.2 | c.1219A>C | p.Ser407Arg | missense_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASL | ENST00000304874.14 | c.1297A>C | p.Ser433Arg | missense_variant | 17/17 | 1 | NM_000048.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461522Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727086
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Argininosuccinate lyase deficiency Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2021 | This sequence change replaces serine with arginine at codon 433 of the ASL protein (p.Ser433Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829, 30285816). ClinVar contains an entry for this variant (Variation ID: 203621). 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. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Oct 13, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 13, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at