rs140578009

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001875.5(CPS1):c.4126G>A(p.Gly1376Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,613,610 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. G1376G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 31 hom., cov: 33)

Exomes 𝑓: 0.014 ( 174 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.38

Publications

24 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=0.0067127645).

BP6

Variant 2-210674926-G-A is Benign according to our data. Variant chr2-210674926-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258484.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0127 (1939/152234) while in subpopulation AMR AF = 0.0158 (242/15282). AF 95% confidence interval is 0.0148. There are 31 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5 link	c.4126G>A	p.Gly1376Ser	missense_variant	Exon 35 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.4126G>A	p.Gly1376Ser	missense_variant	Exon 35 of 38	1	NM_001875.5	ENSP00000233072.5		P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1936

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0131

AC:

3283

AN:

251254

AF XY:

0.0132

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0245

GnomAD4 exome

AF:

0.0137

AC:

20051

AN:

1461376

Hom.:

174

Cov.:

AF XY:

0.0136

AC XY:

9875

AN XY:

727016

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33472

American (AMR)

AF:

0.0125

AC:

561

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

795

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00473

AC:

408

AN:

86246

European-Finnish (FIN)

AF:

0.0315

AC:

1683

AN:

53402

Middle Eastern (MID)

AF:

0.0361

AC:

208

AN:

5758

European-Non Finnish (NFE)

AF:

0.0139

AC:

15419

AN:

1111612

Other (OTH)

AF:

0.0147

AC:

889

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

895

1789

2684

3578

4473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

570

1140

1710

2280

2850

<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:

0.0127

AC:

1939

AN:

152234

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

984

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41542

American (AMR)

AF:

0.0158

AC:

242

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

123

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00664

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0293

AC:

311

AN:

10604

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0156

AC:

1063

AN:

68012

Other (OTH)

AF:

0.0170

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0139

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0118

AC:

1430

EpiCase

AF:

0.0175

EpiControl

AF:

0.0176

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Uncertain:1Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Mar 18, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CPS1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;T;.

Eigen

Benign

0.036

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.57

.;N;.

PhyloP100

4.4

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.64

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0070

.;B;.

Vest4

0.074

MPC

0.23

ClinPred

0.0090

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.51

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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