NM_001875.5:c.4275-10A>G

Variant names:

• chr2-210676997-A-G
• rs41272673
• NM_001875.5:c.4275-10A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):​c.4275-10A>G variant causes a 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 intron
• Scores: Splicing: ADA: 0.00007870
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.161
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 203646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.4275-10A>G		intron_variant	Intron 36 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.4275-10A>G		intron_variant	Intron 36 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4852 AN: 152070 Hom.: 119 Cov.: 32

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

GnomAD2 exomes AF: 0.0331 AC: 8307 AN: 251158 AF XY: 0.0333

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 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.: 30 AF XY: 0.0430 AC XY: 31213 AN XY: 726400

African (AFR) AF: 0.00745 AC: 249 AN: 33432

American (AMR) AF: 0.0275 AC: 1231 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 1046 AN: 26130

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39656

South Asian (SAS) AF: 0.00901 AC: 777 AN: 86228

European-Finnish (FIN) AF: 0.0370 AC: 1973 AN: 53394

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5766

European-Non Finnish (NFE) AF: 0.0510 AC: 56593 AN: 1110148

Other (OTH) AF: 0.0397 AC: 2394 AN: 60334

GnomAD4 genome AF: 0.0319 AC: 4853 AN: 152186 Hom.: 120 Cov.: 32 AF XY: 0.0305 AC XY: 2269 AN XY: 74402

African (AFR) AF: 0.00891 AC: 370 AN: 41538

American (AMR) AF: 0.0300 AC: 459 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4826

European-Finnish (FIN) AF: 0.0380 AC: 403 AN: 10594

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0495 AC: 3366 AN: 67980

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0402 Hom.: 173

Bravo AF: 0.0312

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:5

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

not specified Benign:4

Mar 14, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2014

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. -

-

Clinical Genetics, Academic Medical Center

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.3
DANN	Benign	0.77
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41272673; hg19: chr2-211541721;