rs1047891

Positions:

chr2-210675783-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

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. 13/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 1.82

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]

CPS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain MGS-like (size 145) in uniprot entity CPSM_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) 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	Protein	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.4217C>A	p.Thr1406Asn	missense_variant	36/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.4217C>A	p.Thr1406Asn	missense_variant	36/38	1	NM_001875.5	ENSP00000233072	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49578

AN:

151970

Hom.:

8188

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.309

AC XY:

223650

AN XY:

724140

show subpopulations

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.:

AF XY:

0.327

AC XY:

24287

AN XY:

74346

show subpopulations

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:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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+	-	- -
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. -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital hyperammonemia, type I

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

.;T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

0.074

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

.;L;.

MutationTaster

Benign

0.92

P;P;P

PrimateAI

Uncertain

0.57

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over