rs577707531

Variant names:

• chr2-210642675-GA-G
• rs577707531
• NM_001875.5:c.3141+15delA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001875.5(CPS1):​c.3141+15delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 1,609,884 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (68 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.228
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 2-210642675-GA-G is Benign according to our data. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030. Variant chr2-210642675-GA-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 334030.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00617 (934/151400) while in subpopulation NFE AF = 0.00869 (589/67786). AF 95% confidence interval is 0.00811. There are 7 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.3141+15delA		intron_variant	Intron 25 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.3141+11delA		intron_variant	Intron 25 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 934 AN: 151282 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00638

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.00897

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00869

Gnomad OTH AF: 0.00965

GnomAD2 exomes AF: 0.00709 AC: 1749 AN: 246808 AF XY: 0.00731

Gnomad AFR exome AF: 0.000824

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00797 AC: 11624 AN: 1458484 Hom.: 68 Cov.: 30 AF XY: 0.00780 AC XY: 5661 AN XY: 725496

African (AFR) AF: 0.000962 AC: 32 AN: 33252

American (AMR) AF: 0.00376 AC: 167 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 519 AN: 25996

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.000827 AC: 71 AN: 85850

European-Finnish (FIN) AF: 0.0107 AC: 569 AN: 53332

Middle Eastern (MID) AF: 0.00506 AC: 29 AN: 5734

European-Non Finnish (NFE) AF: 0.00878 AC: 9741 AN: 1110082

Other (OTH) AF: 0.00822 AC: 495 AN: 60202

GnomAD4 genome AF: 0.00617 AC: 934 AN: 151400 Hom.: 7 Cov.: 32 AF XY: 0.00623 AC XY: 461 AN XY: 73978

African (AFR) AF: 0.00143 AC: 59 AN: 41296

American (AMR) AF: 0.00637 AC: 97 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4790

European-Finnish (FIN) AF: 0.00897 AC: 93 AN: 10370

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00869 AC: 589 AN: 67786

Other (OTH) AF: 0.00955 AC: 20 AN: 2094

Alfa AF: 0.00865 Hom.: 3

Bravo AF: 0.00535

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CPS1: BS2 -

Apr 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: c.3141+15delA in CPS1 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this do not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.007693 (831/108016chrs tested), predominantly in individuals of European descent (0.01209; 715/ 59126 chrs tested), including two homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0015%, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Apr 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18666241) -

Congenital hyperammonemia, type I Uncertain:1 Benign:2

Sep 27, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs577707531; hg19: chr2-211507399;