rs150485422

Variant names:

• chr2-210640009-A-G
• rs150485422
• NM_001875.5:c.2909A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001875.5(CPS1):​c.2909A>G​(p.Asn970Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,611,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N970D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.90
• Publications: 3 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=0.030182421).
• BP6: Variant 2-210640009-A-G is Benign according to our data. Variant chr2-210640009-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 567695.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000368 (56/152294) while in subpopulation AFR AF = 0.0012 (50/41556). AF 95% confidence interval is 0.000937. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2909A>G	p.Asn970Ser	missense	Exon 24 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.2942A>G	p.Asn981Ser	missense	Exon 25 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.2909A>G	p.Asn970Ser	missense	Exon 25 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.2909A>G	p.Asn970Ser	missense	Exon 24 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.2927A>G	p.Asn976Ser	missense	Exon 25 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.1556A>G	p.Asn519Ser	missense	Exon 14 of 28	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251146 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000167 AC: 243 AN: 1458926 Hom.: 0 Cov.: 28 AF XY: 0.000153 AC XY: 111 AN XY: 726034

African (AFR) AF: 0.00141 AC: 47 AN: 33398

American (AMR) AF: 0.0000671 AC: 3 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000163 AC: 181 AN: 1109880

Other (OTH) AF: 0.000166 AC: 10 AN: 60292

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74486

African (AFR) AF: 0.00120 AC: 50 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000344

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Congenital hyperammonemia, type I (3)
-	1	-	CPS1-related disorder (1)
-	1	-	Inborn genetic diseases (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	0.062
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	-0.72	N
PhyloP100		2.9
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.26
Sift	Benign	0.69	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.037
MVP		0.90
MPC		0.18
ClinPred		0.035	T
GERP RS		5.4
Varity_R		0.13
gMVP		0.33
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150485422; hg19: chr2-211504733;