Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001875.5(CPS1):c.2265C>A(p.Ser755Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,612,368 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S755S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 19 hom., cov: 32)

Exomes 𝑓: 0.013 ( 177 hom. )

Consequence

CPS1
NM_001875.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.59

Publications

10 publications found

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 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

CPS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-210608433-C-A is Benign according to our data. Variant chr2-210608433-C-A is described in ClinVar as Benign. ClinVar VariationId is 258478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.59 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1818/151904) while in subpopulation NFE AF = 0.0172 (1168/67886). AF 95% confidence interval is 0.0164. There are 19 homozygotes in GnomAd4. There are 947 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPS1	NM_001875.5	MANE Select	c.2265C>A	p.Ser755Ser	synonymous	Exon 19 of 38	NP_001866.2
CPS1	NM_001369256.1		c.2298C>A	p.Ser766Ser	synonymous	Exon 20 of 39	NP_001356185.1
CPS1	NM_001122633.3		c.2265C>A	p.Ser755Ser	synonymous	Exon 20 of 39	NP_001116105.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPS1	ENST00000233072.10	TSL:1 MANE Select	c.2265C>A	p.Ser755Ser	synonymous	Exon 19 of 38	ENSP00000233072.5
CPS1	ENST00000430249.7	TSL:1	c.2283C>A	p.Ser761Ser	synonymous	Exon 20 of 39	ENSP00000402608.2
CPS1	ENST00000451903.3	TSL:1	c.912C>A	p.Ser304Ser	synonymous	Exon 9 of 28	ENSP00000406136.2

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1820

AN:

151786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00493

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0390

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.00911

GnomAD2 exomes

AF:

0.0125

AC:

3137

AN:

250836

AF XY:

0.0124

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00403

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0395

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0128

GnomAD4 exome

AF:

0.0131

AC:

19144

AN:

1460464

Hom.:

177

Cov.:

AF XY:

0.0130

AC XY:

9427

AN XY:

726600

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

33374

American (AMR)

AF:

0.00426

AC:

190

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

406

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86228

European-Finnish (FIN)

AF:

0.0387

AC:

2064

AN:

53402

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0141

AC:

15614

AN:

1111058

Other (OTH)

AF:

0.0114

AC:

689

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1035

2069

3104

4138

5173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

528

1056

1584

2112

2640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0120

AC:

1818

AN:

151904

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

947

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

41480

American (AMR)

AF:

0.00492

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0390

AC:

413

AN:

10594

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0172

AC:

1168

AN:

67886

Other (OTH)

AF:

0.00901

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

186

278

371

464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00868

EpiCase

AF:

0.0118

EpiControl

AF:

0.0135

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital hyperammonemia, type I (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.056

(source)

DANN

Benign

0.63

PhyloP100

-1.6

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over