rs141373204
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2
The NM_001875.5(CPS1):c.3643A>G(p.Ile1215Val) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,611,068 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001875.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CPS1 | NM_001875.5 | c.3643A>G | p.Ile1215Val | missense_variant | Exon 30 of 38 | ENST00000233072.10 | NP_001866.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00126 AC: 188AN: 149584Hom.: 2 Cov.: 28
GnomAD3 exomes AF: 0.00159 AC: 401AN: 251480Hom.: 1 AF XY: 0.00160 AC XY: 218AN XY: 135914
GnomAD4 exome AF: 0.00110 AC: 1610AN: 1461390Hom.: 9 Cov.: 35 AF XY: 0.00115 AC XY: 838AN XY: 727046
GnomAD4 genome AF: 0.00126 AC: 188AN: 149678Hom.: 2 Cov.: 28 AF XY: 0.00113 AC XY: 82AN XY: 72814
ClinVar
Submissions by phenotype
Congenital hyperammonemia, type I Uncertain:5Benign:2
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not provided Uncertain:4
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The I1215V variant has been reported previously in a patient with carbamoylphosphate synthetase I (CPS1) deficiency who also harbored a second variant in the CPS1 gene (Kurokawa et al. 2007). The I1215V variant is observed in 31/11564 (0.27%) alleles from individuals of Latino background, in the ExAC dataset including a homozygous individual (Lek et al., 2016). The I1215V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine and Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
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not specified Uncertain:1
Variant summary: CPS1 c.3643A>G (p.Ile1215Val) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) 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 0.0016 in 251480 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency (0.0016 vs 0.0016), allowing no conclusion about variant significance. The variant allele was found at a frequency of 0.0016 in 251480 control chromosomes, predominantly at a frequency of 0.0018 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3643A>G has been reported in the literature in at-least one individual affected with Carbamoylphosphate Synthetase I Deficiency (example, Kurokawa_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Carbamoylphosphate Synthetase I Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Pulmonary hypertension, neonatal, susceptibility to;C4082171:Congenital hyperammonemia, type I Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at