rs141373204

chr2-210656609-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_001875.5(CPS1):c.3643A>G(p.Ile1215Val) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,611,068 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 28)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 5.82

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 -7 ACMG points.

• PM1: In a domain ATP-grasp 2 (size 191) in uniprot entity CPSM_HUMAN there are 41 pathogenic changes around while only 15 benign (73%) in NM_001875.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0088790655).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00126 (188/149678) while in subpopulation AMR AF= 0.00235 (35/14884). AF 95% confidence interval is 0.00174. There are 2 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.3643A>G	p.Ile1215Val	missense_variant	30/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.3643A>G	p.Ile1215Val	missense_variant	30/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 188 AN: 149584 Hom.: 2 Cov.: 28

Gnomad AFR AF: 0.000124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.0171

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00169

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0292

Gnomad NFE AF: 0.000944

Gnomad OTH AF: 0.00391

GnomAD3 exomes AF: 0.00159 AC: 401 AN: 251480 Hom.: 1 AF XY: 0.00160 AC XY: 218 AN XY: 135914

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00110 AC: 1610 AN: 1461390 Hom.: 9 Cov.: 35 AF XY: 0.00115 AC XY: 838 AN XY: 727046

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000761

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00126 AC: 188 AN: 149678 Hom.: 2 Cov.: 28 AF XY: 0.00113 AC XY: 82 AN XY: 72814

Gnomad4 AFR AF: 0.000123

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.0171

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00170

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000945

Gnomad4 OTH AF: 0.00388

Alfa AF: 0.00189 Hom.: 3

Bravo AF: 0.00131

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital hyperammonemia, type I Uncertain:5 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	May 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2018	The I1215V variant has been reported previously in a patient with carbamoylphosphate synthetase I (CPS1) deficiency who also harbored a second variant in the CPS1 gene (Kurokawa et al. 2007). The I1215V variant is observed in 31/11564 (0.27%) alleles from individuals of Latino background, in the ExAC dataset including a homozygous individual (Lek et al., 2016). The I1215V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine and Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 03, 2022

Variant summary: CPS1 c.3643A>G (p.Ile1215Val) results in a conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251480 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CPS1 causing Carbamoylphosphate Synthetase I Deficiency (0.0016 vs 0.0016), allowing no conclusion about variant significance. The variant allele was found at a frequency of 0.0016 in 251480 control chromosomes, predominantly at a frequency of 0.0018 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.14 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 Latino origin. c.3643A>G has been reported in the literature in at-least one individual affected with Carbamoylphosphate Synthetase I Deficiency (example, Kurokawa_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Carbamoylphosphate Synthetase I Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Pulmonary hypertension, neonatal, susceptibility to;C4082171:Congenital hyperammonemia, type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.017	D;D;T
Polyphen		0.62	.;P;.
Vest4		0.28
MVP		0.85
MPC		0.20
ClinPred		0.018	T
GERP RS		4.9
Varity_R		0.58
gMVP		0.71

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

Other links and lift over

dbSNP: rs141373204; hg19: chr2-211521333; COSMIC: COSV51822452; COSMIC: COSV51822452;