rs1553519513

chr2-210677953-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001875.5(CPS1):c.4471T>C(p.Tyr1491His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.21

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain MGS-like (size 145) in uniprot entity CPSM_HUMAN there are 27 pathogenic changes around while only 8 benign (77%) in NM_001875.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.4471T>C	p.Tyr1491His	missense_variant	38/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.4471T>C	p.Tyr1491His	missense_variant	38/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 02, 2023

Variant summary: CPS1 c.4471T>C (p.Tyr1491His) results in a conservative amino acid change located in the Methylglyoxal synthase-like domain (IPR011607) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251072 control chromosomes. c.4471T>C has been reported in the literature in an individual affected with late onset Carbamoylphosphate Synthetase I Deficiency (Summar_1998). However, the variant was detected in RNA, and no second variant was identified, making the complete genotype of this individual unclear. Therefore, this report does not provide unequivocal conclusions about association of the variant with Carbamoylphosphate Synthetase I Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function (Pekkala_2010). The most pronounced variant effect results in 10%-<30% of normal Carbamoylphosphate Synthetase enzymatic activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 20578160, 9686343). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Congenital hyperammonemia, type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.0082
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.090	T;T;D
Sift4G	Benign	0.083	T;T;T
Polyphen		0.078	.;B;.
Vest4		0.91
MutPred		0.90		.;Gain of disorder (P = 0.0146);.;
MVP		0.77
MPC		0.94
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.83

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: rs1553519513; hg19: chr2-211542677;