rs1554982824
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_054012.4(ASS1):c.216C>G(p.Phe72Leu) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F72I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_054012.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASS1 | NM_054012.4 | c.216C>G | p.Phe72Leu | missense_variant | 4/15 | ENST00000352480.10 | |
ASS1 | NM_000050.4 | c.216C>G | p.Phe72Leu | missense_variant | 5/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASS1 | ENST00000352480.10 | c.216C>G | p.Phe72Leu | missense_variant | 4/15 | 1 | NM_054012.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Citrullinemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 09, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the ASS1 protein (p.Phe72Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with citrullinemia (PMID: 18925679, 31469252). ClinVar contains an entry for this variant (Variation ID: 551465). 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 not expected to disrupt ASS1 protein function. Studies have shown that this missense change alters ASS1 gene expression (PMID: 31469252). This variant disrupts the p.Phe72 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2024 | Variant summary: ASS1 c.216C>G (p.Phe72Leu) results in a non-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 was absent in 251016 control chromosomes. c.216C>G has been reported in the literature in homozygous individuals affected with Citrullinemia Type 1, including at least one individual with mild phenotypic presentation (e.g. Dimmock_2008, Zielonka_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduction in mRNA and protein levels and ~80% of normal enzymatic activity (e.g. Zielonka_2019). The following publications have been ascertained in the context of this evaluation (PMID: 18925679, 31469252). ClinVar contains an entry for this variant (Variation ID: 551465). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Citrullinemia type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 11, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at