rs764384490
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001875.5(CPS1):βc.1529delβ(p.Gly510AlafsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. G510G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001875.5 frameshift
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 |
---|---|---|---|---|---|---|---|
CPS1 | NM_001875.5 | c.1529del | p.Gly510AlafsTer5 | frameshift_variant | 14/38 | ENST00000233072.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPS1 | ENST00000233072.10 | c.1529del | p.Gly510AlafsTer5 | frameshift_variant | 14/38 | 1 | NM_001875.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151902Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250518Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135378
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460364Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726536
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Congenital hyperammonemia, type I Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 05, 2023 | This sequence change creates a premature translational stop signal (p.Gly510Alafs*5) in the CPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPS1 are known to be pathogenic (PMID: 21120950). This variant is present in population databases (rs764384490, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with carbamoyl phosphate synthetase I deficiency (PMID: 15617192). This variant is also known as 1528delG (510-514 ARQLX). ClinVar contains an entry for this variant (Variation ID: 553751). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 24, 2022 | Variant summary: CPS1 c.1529delG (p.Gly510AlafsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 250518 control chromosomes. c.1529delG has been reported in the literature in multiple individuals affected with Carbamoylphosphate Synthetase I Deficiency in the homozygous and compound heterozygous state (example: Yamaguchi_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00002, PM2). The variant was observed in trans with a pathogenic variant (NM_001875.4: c.2339G>A) as compound heterozygous (3billion dataset, PM3). The variant has been reported as pathogenic/likely pathogenic without evidence for the classification (ClinVar ID:VCV000553751.1). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pulmonary hypertension, neonatal, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at