rs760714614
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001875.5(CPS1):c.2810T>A(p.Ile937Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
CPS1
NM_001875.5 missense
NM_001875.5 missense
Scores
14
2
1
Clinical Significance
Conservation
PhyloP100: 7.05
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
?
Variant 2-210637824-T-A is Pathogenic according to our data. Variant chr2-210637824-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557702.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPS1 | NM_001875.5 | c.2810T>A | p.Ile937Asn | missense_variant | 22/38 | ENST00000233072.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPS1 | ENST00000233072.10 | c.2810T>A | p.Ile937Asn | missense_variant | 22/38 | 1 | NM_001875.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152102Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251244Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135774
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461618Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727102
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital hyperammonemia, type I Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 11, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 937 of the CPS1 protein (p.Ile937Asn). This variant is present in population databases (rs760714614, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of carbamoyl phosphate synthetase 1 deficiency (PMID: 24813853, 32718099). ClinVar contains an entry for this variant (Variation ID: 557702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CPS1 function (PMID: 24813853). 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. - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2018 | - - |
Pulmonary hypertension, neonatal, susceptibility to Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MutPred
0.83
.;Gain of disorder (P = 0.0129);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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