rs200569046

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001875.5(CPS1):c.3626T>C(p.Met1209Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,612,688 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00021 ( 4 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.52

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 -11 ACMG points.

PM1

In a domain ATP-grasp 2 (size 191) in uniprot entity CPSM_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_001875.5

BP4

Computational evidence support a benign effect (MetaRNN=0.014570594).

BP6

Variant 2-210656592-T-C is Benign according to our data. Variant chr2-210656592-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210758.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000212 (32/150840) while in subpopulation EAS AF= 0.0039 (20/5124). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5 link	c.3626T>C	p.Met1209Thr	missense_variant	Exon 30 of 38	ENST00000233072.10	NP_001866.2	P31327-1A0A024R454Q6PEK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 link	c.3626T>C	p.Met1209Thr	missense_variant	Exon 30 of 38	1	NM_001875.5	ENSP00000233072.5		P31327-1

Frequencies

GnomAD3 genomes

AF:

0.000212

AC:

AN:

150732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00389

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00107

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000488

GnomAD3 exomes

AF:

0.000545

AC:

137

AN:

251476

Hom.:

AF XY:

0.000508

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00576

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000207

AC:

302

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

146

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00602

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000212

AC:

AN:

150840

Hom.:

Cov.:

AF XY:

0.000272

AC XY:

AN XY:

73580

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00390

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00107

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000483

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.000478

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Uncertain:1Benign:3

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jun 10, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

0.0093

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

.;D;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

-0.14

.;N;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.1

N;N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.27

.;B;.

Vest4

0.80

MVP

0.93

MPC

0.28

ClinPred

0.20

GERP RS

5.9

Varity_R

0.81

gMVP

0.88

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

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