rs114819130

Positions:

• chr2-210577488-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001875.5(CPS1):​c.449G>A​(p.Gly150Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0104 in 1,613,504 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G150G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0061 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (114 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.65

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a region_of_interest Anthranilate phosphoribosyltransferase homolog (size 179) in uniprot entity CPSM_HUMAN there are 27 pathogenic changes around while only 9 benign (75%) in NM_001875.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.014847696).
• BP6: Variant 2-210577488-G-A is Benign according to our data. Variant chr2-210577488-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334013.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5, Benign=2}. Variant chr2-210577488-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00613 (933/152128) while in subpopulation NFE AF= 0.0101 (685/67998). AF 95% confidence interval is 0.00945. There are 4 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.449G>A	p.Gly150Glu	missense_variant	4/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.449G>A	p.Gly150Glu	missense_variant	4/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 933 AN: 152010 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00414

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00639 AC: 1605 AN: 251346 Hom.: 4 AF XY: 0.00635 AC XY: 863 AN XY: 135840

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.00937

Gnomad OTH exome AF: 0.00816

GnomAD4 exome AF: 0.0108 AC: 15828 AN: 1461376 Hom.: 114 Cov.: 31 AF XY: 0.0107 AC XY: 7780 AN XY: 727006

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00424

Gnomad4 FIN exome AF: 0.00404

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00613 AC: 933 AN: 152128 Hom.: 4 Cov.: 32 AF XY: 0.00565 AC XY: 420 AN XY: 74350

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00413

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00935 Hom.: 12

Bravo AF: 0.00620

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00633 AC: 768

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital hyperammonemia, type I Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CPS1: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	This variant is associated with the following publications: (PMID: 18666241) -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CPS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;D;D
Eigen	Benign	0.16
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T;D;D;D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D;D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.028	D;D;D;T
Polyphen		0.53	.;.;P;.
Vest4		0.76, 0.72, 0.71
MVP		0.95
MPC		0.58
ClinPred		0.063	T
GERP RS		4.4
Varity_R		0.88
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs114819130; hg19: chr2-211442212; COSMIC: COSV99028192; COSMIC: COSV99028192;