rs895822620
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The ENST00000352480.10(ASS1):c.262C>A(p.Leu88Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,384 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L88L) has been classified as Likely benign.
Frequency
Consequence
ENST00000352480.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASS1 | NM_054012.4 | c.262C>A | p.Leu88Ile | missense_variant | 4/15 | ENST00000352480.10 | NP_446464.1 | |
ASS1 | NM_000050.4 | c.262C>A | p.Leu88Ile | missense_variant | 5/16 | NP_000041.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASS1 | ENST00000352480.10 | c.262C>A | p.Leu88Ile | missense_variant | 4/15 | 1 | NM_054012.4 | ENSP00000253004 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250838Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135662
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460384Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726500
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Citrullinemia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2024 | Variant summary: ASS1 c.262C>A (p.Leu88Ile) results in a conservative amino acid change located in the Arginosuccinate synthase-like, N-terminal domain (IPR048267) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250838 control chromosomes (gnomAD). c.262C>A has been reported in the literature in individuals affected with Citrullinemia (Dimmock_2008, Barends_2014). These data indicate that the variant is likely to be associated with disease. 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: 18925679, 25047749). ClinVar contains an entry for this variant (Variation ID: 426661). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 10, 2023 | This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 88 of the ASS1 protein (p.Leu88Ile). This missense change has been observed in individual(s) with elevated citrulline or ASS1 enzyme deficiency in skin fibroblasts (PMID: 18925679, 25047749; Invitae). ClinVar contains an entry for this variant (Variation ID: 426661). 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. For these reasons, this variant has been classified as Pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2017 | The L88I missense variant in the ASS1 gene has been previously reported in a homozygous state intwo asymptomatic individuals with abnormal newborn screening and elevated citrulline (Dimmock etal., 2008; Barends et al., 2014). The L88I variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L88I variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damagingto the protein structure/function. Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant. - |
Citrullinemia type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 05, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at