rs571576756
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_054012.4(ASS1):c.920G>A(p.Arg307His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307C) 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.920G>A | p.Arg307His | missense_variant | 12/15 | ENST00000352480.10 | |
ASS1 | NM_000050.4 | c.920G>A | p.Arg307His | missense_variant | 13/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASS1 | ENST00000352480.10 | c.920G>A | p.Arg307His | missense_variant | 12/15 | 1 | NM_054012.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152022Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251430Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135890
GnomAD4 exome AF: 0.0000752 AC: 110AN: 1461816Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 727208
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
Citrullinemia type I Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 27, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 19, 2022 | Variant summary: ASS1 c.920G>A (p.Arg307His) results in a non-conservative amino acid change located in the catalytic/multimerization domain (IPR024074) 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 5.2e-05 in 251430 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (5.2e-05 vs 0.0041), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.920G>A in individuals affected with Citrullinemia Type I and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Citrullinemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 03, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 307 of the ASS1 protein (p.Arg307His). This variant is present in population databases (rs571576756, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ASS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 528371). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Arg307 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14680976; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at