rs1553511785
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_001875.5(CPS1):c.1307G>A(p.Gly436Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_001875.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPS1 | NM_001875.5 | c.1307G>A | p.Gly436Asp | missense_variant | 13/38 | ENST00000233072.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPS1 | ENST00000233072.10 | c.1307G>A | p.Gly436Asp | missense_variant | 13/38 | 1 | NM_001875.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459690Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726228
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Congenital hyperammonemia, type I Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 CPS1 protein function. ClinVar contains an entry for this variant (Variation ID: 477849). This missense change has been observed in individual(s) with carbamoyl phosphate synthetase I deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 436 of the CPS1 protein (p.Gly436Asp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at