rs781088670
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001875.5(CPS1):c.2227del(p.Leu743Ter) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A742A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CPS1
NM_001875.5 frameshift
NM_001875.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.77
Genes affected
CPS1 (HGNC:2323): (carbamoyl-phosphate synthase 1) The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-210608392-GC-G is Pathogenic according to our data. Variant chr2-210608392-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557529.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-210608392-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPS1 | NM_001875.5 | c.2227del | p.Leu743Ter | frameshift_variant | 19/38 | ENST00000233072.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPS1 | ENST00000233072.10 | c.2227del | p.Leu743Ter | frameshift_variant | 19/38 | 1 | NM_001875.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250752Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135536
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460218Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726496
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital hyperammonemia, type I Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 28, 2018 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at