Menu
GeneBe

rs765484849

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_001875.5(CPS1):c.2740G>C(p.Asp914His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 780,854 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D914G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

14
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 8.80
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a helix (size 7) in uniprot entity CPSM_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001875.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 2-210637754-G-C is Pathogenic according to our data. Variant chr2-210637754-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555253.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr2-210637754-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CPS1NM_001875.5 linkuse as main transcriptc.2740G>C p.Asp914His missense_variant 22/38 ENST00000233072.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CPS1ENST00000233072.10 linkuse as main transcriptc.2740G>C p.Asp914His missense_variant 22/381 NM_001875.5 P1P31327-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251354
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135852
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000636
AC:
4
AN:
628660
Hom.:
0
Cov.:
32
AF XY:
0.00000584
AC XY:
2
AN XY:
342474
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000857
Gnomad4 OTH exome
AF:
0.0000302
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeApr 06, 2023For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp914 amino acid residue in CPS1. Other variant(s) that disrupt this residue have been observed in individuals with CPS1-related conditions (PMID: 24813853), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects CPS1 function (PMID: 24813853). 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: 555253). This missense change has been observed in individuals with clinical features of carbamoylphosphate synthetase I deficiency (PMID: 31435610, 33309754; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 914 of the CPS1 protein (p.Asp914His). -
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Jun 02, 2021- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 25, 2023Variant summary: CPS1 c.2740G>C (p.Asp914His) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase, large subunit oligomerisation domain (IPR005480) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251354 control chromosomes. c.2740G>C has been reported in the literature in neonates or infants affected with Carbamoylphosphate Synthetase I Deficiency (e.g. Talebi_2019, Haberle_2011, Diez-Fernandez_2014, Nitzahn_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal CPS1 enzymatic activity (e.g. Diez-Fernandez_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24813853, 21120950, 31435610, 34970092). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1), likely pathogenic (n=1), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 26, 2017- -
Pulmonary hypertension, neonatal, susceptibility to Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 28, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
28
Dann
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.48
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-6.9
D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
1.0
MutPred
0.95
.;Gain of MoRF binding (P = 0.0377);.;
MVP
0.99
MPC
0.91
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.99
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs765484849; hg19: chr2-211502478; API