rs76340296

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000233072.10(CPS1):c.3355G>A(p.Ala1119Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00248 in 1,613,204 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 51 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 42 hom. )

Consequence

CPS1
ENST00000233072.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain ATP-grasp 2 (size 191) in uniprot entity CPSM_HUMAN there are 42 pathogenic changes around while only 15 benign (74%) in ENST00000233072.10

BP4

Computational evidence support a benign effect (MetaRNN=0.0064868033).

BP6

Variant 2-210648491-G-A is Benign according to our data. Variant chr2-210648491-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210648491-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2042/152282) while in subpopulation AFR AF= 0.0464 (1926/41552). AF 95% confidence interval is 0.0446. There are 51 homozygotes in gnomad4. There are 959 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.3355G>A	p.Ala1119Thr	missense_variant	27/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.3355G>A	p.Ala1119Thr	missense_variant	27/38	1	NM_001875.5	ENSP00000233072	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2040

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0464

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00337

AC:

847

AN:

251162

Hom.:

AF XY:

0.00250

AC XY:

340

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.0475

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00135

AC:

1965

AN:

1460922

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

878

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.0488

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00283

GnomAD4 genome

AF:

0.0134

AC:

2042

AN:

152282

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

959

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0464

Gnomad4 AMR

AF:

0.00575

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00231

Hom.:

Bravo

AF:

0.0155

ESP6500AA

AF:

0.0472

AC:

208

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00420

AC:

510

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.6

.;H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.64

Sift

Benign

0.034

D;D;T

Sift4G

Benign

0.10

T;T;T

Polyphen

0.37

.;B;.

Vest4

0.44

MVP

0.96

MPC

0.31

ClinPred

0.078

GERP RS

6.2

Varity_R

0.63

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over