rs114819130

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001875.5(CPS1):c.449G>A(p.Gly150Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0104 in 1,613,504 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G150G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0061 ( 4 hom., cov: 32)

Exomes 𝑓: 0.011 ( 114 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.65

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

carbamoyl phosphate synthetase I deficiency disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

CPS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014847696).

BP6

Variant 2-210577488-G-A is Benign according to our data. Variant chr2-210577488-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334013.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00613 (933/152128) while in subpopulation NFE AF = 0.0101 (685/67998). AF 95% confidence interval is 0.00945. There are 4 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5 link	c.449G>A	p.Gly150Glu	missense_variant	Exon 4 of 38	ENST00000233072.10	NP_001866.2	P31327-1A0A024R454Q6PEK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 link	c.449G>A	p.Gly150Glu	missense_variant	Exon 4 of 38	1	NM_001875.5	ENSP00000233072.5		P31327-1

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

933

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00414

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00499

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00639

AC:

1605

AN:

251346

AF XY:

0.00635

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00383

Gnomad NFE exome

AF:

0.00937

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.0108

AC:

15828

AN:

1461376

Hom.:

114

Cov.:

AF XY:

0.0107

AC XY:

7780

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33458

American (AMR)

AF:

0.00400

AC:

179

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

310

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00424

AC:

366

AN:

86256

European-Finnish (FIN)

AF:

0.00404

AC:

216

AN:

53420

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0126

AC:

14019

AN:

1111568

Other (OTH)

AF:

0.0112

AC:

674

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

755

1510

2266

3021

3776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

568

1136

1704

2272

2840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00613

AC:

933

AN:

152128

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

420

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41528

American (AMR)

AF:

0.00413

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.00499

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00255

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

685

AN:

67998

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00878

Hom.:

Bravo

AF:

0.00620

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.00633

AC:

768

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Benign:4

Jan 10, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18666241) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CPS1: BS1, BS2 -

Inborn genetic diseases

Benign:1

May 09, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CPS1-related disorder

Benign:1

Oct 12, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;.;D;D

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

T;D;D;D

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.1

.;.;L;.

PhyloP100

3.7

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.8

D;D;D;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.028

D;D;D;T

Polyphen

0.53

.;.;P;.

Vest4

0.76, 0.72, 0.71

MVP

0.95

MPC

0.58

ClinPred

0.063

GERP RS

4.4

Varity_R

0.88

gMVP

0.91

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over