rs201623252
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_054012.4(ASS1):c.380G>A(p.Arg127Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,924 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_054012.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASS1 | NM_054012.4 | c.380G>A | p.Arg127Gln | missense_variant | 5/15 | ENST00000352480.10 | |
ASS1 | NM_000050.4 | c.380G>A | p.Arg127Gln | missense_variant | 6/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASS1 | ENST00000352480.10 | c.380G>A | p.Arg127Gln | missense_variant | 5/15 | 1 | NM_054012.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152044Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251448Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727242
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152044Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74250
ClinVar
Submissions by phenotype
Citrullinemia type I Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 08, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Citrullinemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 04, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg127 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19006241, 23246278, 27287393). 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 ASS1 protein function. ClinVar contains an entry for this variant (Variation ID: 623334). This missense change has been observed in individual(s) with citrulinemia (PMID: 14680976, 23099195, 28111830, 31208364). This variant is present in population databases (rs201623252, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 127 of the ASS1 protein (p.Arg127Gln). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2023 | Published functional studies found this variant is associated with significantly reduced enzyme activity compared to wild-type (Diez-Fernandez C et al., 2016; Zielonka M et al., 2019); Identified in individuals with positive newborn screening for citrullinemia who were also heterozygous for another variant in the ASS1 gene (Haberle J et al., 2003; Woo HI et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29896748, 31469252, 29273096, 25443352, 36263152, 31208364, 27915290, 26659599, 28111830, 23099195, 19006241, 24508627, 27287393, 14680976) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at