rs1047883

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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:14

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.1030A>G	p.Thr344Ala	missense_variant	10/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.1030A>G	p.Thr344Ala	missense_variant	10/38	1	NM_001875.5	P1	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

GnomAD3 exomes

AF:

0.567

AC:

141566

AN:

249584

Hom.:

40570

AF XY:

0.573

AC XY:

77293

AN XY:

134908

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 SAS exome

AF:

0.601

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

Gnomad4 AMR exome

AF:

0.480

Gnomad4 ASJ exome

AF:

0.608

Gnomad4 EAS exome

AF:

0.551

Gnomad4 SAS exome

AF:

0.605

Gnomad4 FIN exome

AF:

0.627

Gnomad4 NFE exome

AF:

0.559

Gnomad4 OTH exome

AF:

0.581

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

Gnomad4 AMR

AF:

0.526

Gnomad4 ASJ

AF:

0.614

Gnomad4 EAS

AF:

0.567

Gnomad4 SAS

AF:

0.616

Gnomad4 FIN

AF:

0.637

Gnomad4 NFE

AF:

0.564

Gnomad4 OTH

AF:

0.582

Alfa

AF:

0.566

Hom.:

41143

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:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, 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	GeneDx	Jul 25, 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. -

Congenital hyperammonemia, type I

Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

clinical testing

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

May 14, 2017

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

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

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

MutationTaster

Benign

1.0

P;P

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

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