rs575001023
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_054012.4(ASS1):c.257G>A(p.Arg86His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,430 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. R86C) has been classified as Pathogenic.
Frequency
Consequence
NM_054012.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250838Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135670
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460258Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726456
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Citrullinemia Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg86 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1943692, 25433810). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASS1 protein function. ClinVar contains an entry for this variant (Variation ID: 265960). This missense change has been observed in individual(s) with citrullinemia type I (PMID: 12815590, 28132756). This variant is present in population databases (rs575001023, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 86 of the ASS1 protein (p.Arg86His). -
Variant summary: ASS1 c.257G>A (p.Arg86His) results in a non-conservative amino acid change located in the Arginosuccinate synthase N-terminal HUP domain (IPR048267) of the encoded protein sequence. Three 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 250838 control chromosomes. c.257G>A has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Citrullinemia Type I (e.g. Gao_2003, Kose_2017, Liu_2021). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.256C>T, p.Arg86Cys), supporting the critical relevance of codon 86 to ASS1 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12815590, 15580409, 28132756, 33617202). ClinVar contains an entry for this variant (Variation ID: 265960). Based on the evidence outlined above, the variant was classified as pathogenic. -
Citrullinemia type I Pathogenic:1Other:1
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not provided Pathogenic:1
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12815590, 20301631, 19006241, 24508627, 18925679, 28132756, 28111830) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at