NM_001875.5:c.1627G>T

Variant names:

• chr2-210600632-G-T
• rs142369181
• NM_001875.5:c.1627G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001875.5(CPS1):​c.1627G>T​(p.Ala543Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,300 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A543T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.1627G>T	p.Ala543Ser	missense	Exon 15 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.1660G>T	p.Ala554Ser	missense	Exon 16 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.1627G>T	p.Ala543Ser	missense	Exon 16 of 39	NP_001116105.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.1627G>T	p.Ala543Ser	missense	Exon 15 of 38	ENSP00000233072.5
	CPS1	ENST00000430249.7	TSL:1	c.1645G>T	p.Ala549Ser	missense	Exon 16 of 39	ENSP00000402608.2
	CPS1	ENST00000451903.3	TSL:1	c.274G>T	p.Ala92Ser	missense	Exon 5 of 28	ENSP00000406136.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460300 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726502

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110986

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.53
Sift	Benign	0.36	T
Sift4G	Benign	0.55	T
Polyphen		0.15	B
Vest4		0.65
MutPred		0.43		Gain of disorder (P = 0.0151)
MVP		0.88
MPC		0.29
ClinPred		0.51	D
GERP RS		4.2
Varity_R		0.49
gMVP		0.83
Mutation Taster		=42/58	disease causing

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: rs142369181; hg19: chr2-211465356; COSMIC: COSV51800866; COSMIC: COSV51800866;