rs1047891

chr2-210675783-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):c.4217C>A(p.Thr1406Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,606,716 control chromosomes in the GnomAD database, including 79,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8199 hom., cov: 33)
  • Exomes 𝑓: 0.31 (70851 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain MGS-like (size 145) in uniprot entity CPSM_HUMAN there are 27 pathogenic changes around while only 8 benign (77%) in NM_001875.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.003946036).
• BP6: Variant 2-210675783-C-A is Benign according to our data. Variant chr2-210675783-C-A is described in ClinVar as [Benign]. Clinvar id is 128852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210675783-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.4217C>A	p.Thr1406Asn	missense_variant	36/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.4217C>A	p.Thr1406Asn	missense_variant	36/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49578 AN: 151970 Hom.: 8188 Cov.: 33

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.324

GnomAD3 exomes AF: 0.304 AC: 76336 AN: 251072 Hom.: 11802 AF XY: 0.305 AC XY: 41322 AN XY: 135678

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.295

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.309 AC: 449492 AN: 1454628 Hom.: 70851 Cov.: 29 AF XY: 0.309 AC XY: 223650 AN XY: 724140

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.326

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.295

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.326 AC: 49617 AN: 152088 Hom.: 8199 Cov.: 33 AF XY: 0.327 AC XY: 24287 AN XY: 74346

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.294

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.321

Alfa AF: 0.319 Hom.: 6939

Bravo AF: 0.326

TwinsUK AF: 0.313 AC: 1161

ALSPAC AF: 0.314 AC: 1212

ESP6500AA AF: 0.364 AC: 1605

ESP6500EA AF: 0.311 AC: 2676

ExAC AF: 0.303 AC: 36847

Asia WGS AF: 0.245 AC: 856 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.304

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital hyperammonemia, type I Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

CARBAMOYL PHOSPHATE SYNTHETASE I POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 2011

- -

Pulmonary hypertension, neonatal, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.10
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.92	P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0090	.;B;.
Vest4		0.054
MPC		0.26
ClinPred		0.0052	T
GERP RS		5.2
Varity_R		0.43
gMVP		0.67

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

Other links and lift over

dbSNP: rs1047891; hg19: chr2-211540507; COSMIC: COSV51808344;