rs765106604

chr2-210674912-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP6

The NM_001875.5(CPS1):c.4112G>A(p.Arg1371Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,446 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1371W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.83

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 Uncertain_significance. Variant got 5 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP6: Variant 2-210674912-G-A is Benign according to our data. Variant chr2-210674912-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579049.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.4112G>A	p.Arg1371Gln	missense_variant	35/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.4112G>A	p.Arg1371Gln	missense_variant	35/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251248 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135790

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1461352 Hom.: 0 Cov.: 29 AF XY: 0.0000440 AC XY: 32 AN XY: 727032

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital hyperammonemia, type I Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.4112G>A (p.R1371Q) alteration is located in exon 35 (coding exon 35) of the CPS1 gene. This alteration results from a G to A substitution at nucleotide position 4112, causing the arginine (R) at amino acid position 1371 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.082	T;T;D
Sift4G	Benign	0.068	T;T;T
Polyphen		0.074	.;B;.
Vest4		0.79
MutPred		0.48		.;Loss of catalytic residue at R1371 (P = 0.0356);.;
MVP		0.84
MPC		0.28
ClinPred		0.11	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.80

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: rs765106604; hg19: chr2-211539636; COSMIC: COSV51802810;