rs4233981

Variant names:

• chr2-210664654-G-C
• rs4233981
• NM_001875.5:c.4002+1457G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001875.5(CPS1):​c.4002+1457G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,042 control chromosomes in the GnomAD database, including 43,501 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43501 hom., cov: 31)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.4002+1457G>C		intron_variant	Intron 33 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.4002+1457G>C		intron_variant	Intron 33 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113813 AN: 151924 Hom.: 43473 Cov.: 31

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.735

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.749 AC: 113894 AN: 152042 Hom.: 43501 Cov.: 31 AF XY: 0.751 AC XY: 55800 AN XY: 74342

African (AFR) AF: 0.600 AC: 24842 AN: 41406

American (AMR) AF: 0.783 AC: 11966 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3468

East Asian (EAS) AF: 0.633 AC: 3271 AN: 5168

South Asian (SAS) AF: 0.812 AC: 3909 AN: 4816

European-Finnish (FIN) AF: 0.840 AC: 8889 AN: 10582

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.819 AC: 55715 AN: 67998

Other (OTH) AF: 0.732 AC: 1543 AN: 2108

Alfa AF: 0.782 Hom.: 5848

Bravo AF: 0.735

Asia WGS AF: 0.685 AC: 2383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.60
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs4233981; hg19: chr2-211529378;