rs141373204

Variant names:

• chr2-210656609-A-G
• rs141373204
• NM_001875.5:c.3643A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. 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
• Publications: 13 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.3643A>G	p.Ile1215Val	missense	Exon 30 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.3676A>G	p.Ile1226Val	missense	Exon 31 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.3643A>G	p.Ile1215Val	missense	Exon 31 of 39	NP_001116105.2	P31327-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.3643A>G	p.Ile1215Val	missense	Exon 30 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.3661A>G	p.Ile1221Val	missense	Exon 31 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2290A>G	p.Ile764Val	missense	Exon 20 of 28	ENSP00000406136.2	P31327-2

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

GnomAD2 exomes AF: 0.00159 AC: 401 AN: 251480 AF XY: 0.00160

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.00170 AC: 76 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 384 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.000761 AC: 846 AN: 1111546

Other (OTH) AF: 0.00295 AC: 178 AN: 60380

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

African (AFR) AF: 0.000123 AC: 5 AN: 40570

American (AMR) AF: 0.00235 AC: 35 AN: 14884

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 59 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00170 AC: 8 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9942

Middle Eastern (MID) AF: 0.0315 AC: 9 AN: 286

European-Non Finnish (NFE) AF: 0.000945 AC: 64 AN: 67756

Other (OTH) AF: 0.00388 AC: 8 AN: 2064

Alfa AF: 0.00173 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	2	Congenital hyperammonemia, type I (7)
-	4	-	not provided (4)
-	1	-	not specified (1)
-	1	-	Pulmonary hypertension, neonatal, susceptibility to;C4082171:Congenital hyperammonemia, type I (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.3	L
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.81	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.017	D
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
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

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