rs41272673

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.4275-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0429 in 1,611,978 control chromosomes in the GnomAD database, including 1,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 120 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1607 hom. )

Consequence

CPS1
NM_001875.5 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00007870

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.161

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 (BayesDel_noAF=-0.64).

BP6

Variant 2-210676997-A-G is Benign according to our data. Variant chr2-210676997-A-G is described in ClinVar as [Benign]. Clinvar id is 203646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210676997-A-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0506 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.4275-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.4275-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001875.5	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4852

AN:

152070

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0302

Gnomad ASJ

AF:

0.0340

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0380

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0331

AC:

8307

AN:

251158

Hom.:

201

AF XY:

0.0333

AC XY:

4525

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00727

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.0389

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00846

Gnomad FIN exome

AF:

0.0350

Gnomad NFE exome

AF:

0.0497

Gnomad OTH exome

AF:

0.0391

GnomAD4 exome

AF:

0.0441

AC:

64356

AN:

1459792

Hom.:

1607

Cov.:

AF XY:

0.0430

AC XY:

31213

AN XY:

726400

show subpopulations

Gnomad4 AFR exome

AF:

0.00745

Gnomad4 AMR exome

AF:

0.0275

Gnomad4 ASJ exome

AF:

0.0400

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00901

Gnomad4 FIN exome

AF:

0.0370

Gnomad4 NFE exome

AF:

0.0510

Gnomad4 OTH exome

AF:

0.0397

GnomAD4 genome

AF:

0.0319

AC:

4853

AN:

152186

Hom.:

120

Cov.:

AF XY:

0.0305

AC XY:

2269

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00891

Gnomad4 AMR

AF:

0.0300

Gnomad4 ASJ

AF:

0.0340

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.0380

Gnomad4 NFE

AF:

0.0495

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0416

Hom.:

Bravo

AF:

0.0312

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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. -
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	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2014	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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2019	Variant summary: CPS1 c.4275-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.033 in 276886 control chromosomes, predominantly at a frequency of 0.048 within the Non-Finnish European subpopulation in the gnomAD database, including 165 homozygotes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 30 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.4275-10A>G in individuals affected with Carbamoylphosphate Synthetase I Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.3

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000079

dbscSNV1_RF

Benign

0.0060

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