rs1047883

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001875.5(CPS1):c.1030A>G(p.Thr344Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,610,050 control chromosomes in the GnomAD database, including 260,102 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.58 ( 25694 hom., cov: 32)

Exomes 𝑓: 0.57 ( 234408 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.266

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024514198).

BP6

Variant 2-210591913-A-G is Benign according to our data. Variant chr2-210591913-A-G is described in ClinVar as [Benign]. Clinvar id is 128849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591913-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5 link	c.1030A>G	p.Thr344Ala	missense_variant	Exon 10 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.1030A>G	p.Thr344Ala	missense_variant	Exon 10 of 38	1	NM_001875.5	ENSP00000233072.5		P31327-1

Frequencies

GnomAD3 genomes

AF:

0.581

AC:

87841

AN:

151172

Hom.:

25660

Cov.:

show subpopulations

Gnomad AFR

AF:

0.612

Gnomad AMI

AF:

0.456

Gnomad AMR

AF:

0.526

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.615

Gnomad FIN

AF:

0.637

Gnomad MID

AF:

0.640

Gnomad NFE

AF:

0.564

Gnomad OTH

AF:

0.580

GnomAD2 exomes

AF:

0.567

AC:

141566

AN:

249584

AF XY:

0.573

show subpopulations

Gnomad AFR exome

AF:

0.613

Gnomad AMR exome

AF:

0.471

Gnomad ASJ exome

AF:

0.618

Gnomad EAS exome

AF:

0.548

Gnomad FIN exome

AF:

0.634

Gnomad NFE exome

AF:

0.566

Gnomad OTH exome

AF:

0.579

GnomAD4 exome

AF:

0.565

AC:

824785

AN:

1458762

Hom.:

234408

Cov.:

AF XY:

0.568

AC XY:

412380

AN XY:

725774

show subpopulations

Gnomad4 AFR exome

AF:

0.621

AC:

20719

AN:

33352

Gnomad4 AMR exome

AF:

0.480

AC:

21388

AN:

44526

Gnomad4 ASJ exome

AF:

0.608

AC:

15853

AN:

26058

Gnomad4 EAS exome

AF:

0.551

AC:

21833

AN:

39626

Gnomad4 SAS exome

AF:

0.605

AC:

52145

AN:

86150

Gnomad4 FIN exome

AF:

0.627

AC:

33325

AN:

53180

Gnomad4 NFE exome

AF:

0.559

AC:

620790

AN:

1109916

Gnomad4 Remaining exome

AF:

0.581

AC:

34999

AN:

60204

Heterozygous variant carriers

19834

39667

59501

79334

99168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

17366

34732

52098

69464

86830

<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:

0.581

AC:

87924

AN:

151288

Hom.:

25694

Cov.:

AF XY:

0.583

AC XY:

43100

AN XY:

73866

show subpopulations

Gnomad4 AFR

AF:

0.613

AC:

0.613013

AN:

0.613013

Gnomad4 AMR

AF:

0.526

AC:

0.525636

AN:

0.525636

Gnomad4 ASJ

AF:

0.614

AC:

0.614228

AN:

0.614228

Gnomad4 EAS

AF:

0.567

AC:

0.566784

AN:

0.566784

Gnomad4 SAS

AF:

0.616

AC:

0.615593

AN:

0.615593

Gnomad4 FIN

AF:

0.637

AC:

0.636781

AN:

0.636781

Gnomad4 NFE

AF:

0.564

AC:

0.56396

AN:

0.56396

Gnomad4 OTH

AF:

0.582

AC:

0.581991

AN:

0.581991

Heterozygous variant carriers

1869

3738

5607

7476

9345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.567

Hom.:

66075

Bravo

AF:

0.579

TwinsUK

AF:

0.565

AC:

2094

ALSPAC

AF:

0.556

AC:

2143

ESP6500AA

AF:

0.639

AC:

2815

ESP6500EA

AF:

0.568

AC:

4881

ExAC

AF:

0.568

AC:

68907

EpiCase

AF:

0.574

EpiControl

AF:

0.579

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 25, 2013

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Congenital hyperammonemia, type I

Benign:6

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

May 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The CPS1 c.1030A>G (p.Thr344Ala) variant located in the glutamine amidotransferase domain (via InterPro) involves the alteration of a non-conserved nucleotide and 2/3 in silico tools (MutationTaster not working at time of scoring and SNPsandGo had a low reliability index, therefore, not captured here) predict a benign outcome. However, these for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 68398/120062 control chromosomes (19535 homozygotes) at a frequency of 0.569689, which is approximately 360 times the estimated maximal expected allele frequency of a pathogenic CPS1 variant (0.0015811), suggesting this variant is likely a benign polymorphism. Furthermore, the observed frequency indicates that the varant of interest is the major allele in the general population. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pulmonary hypertension, neonatal, susceptibility to;C4082171:Congenital hyperammonemia, type I

Benign:1

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.9

DANN

Benign

0.92

DEOGEN2

Pathogenic

0.83

.;D;D

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.042

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

.;L;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.9

D;D;.

REVEL

Benign

0.25

Sift

Benign

0.067

T;T;.

Sift4G

Uncertain

0.036

D;D;T

Polyphen

0.0010

.;B;.

Vest4

0.12

MPC

0.22

ClinPred

0.0075

GERP RS

-0.92

Varity_R

0.40

gMVP

0.31

Mutation Taster

=89/11

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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