Genetic Variant CTPS1:p.Gln167Gln (chr1-40988656-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001905.4(CTPS1):c.501A>G(p.Gln167Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,614,002 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 62 hom., cov: 32)

Exomes 𝑓: 0.017 ( 566 hom. )

Consequence

CTPS1
NM_001905.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.742

Publications

10 publications found

Variant links:

Genes affected

CTPS1 (HGNC:2519): (CTP synthase 1) This gene encodes an enzyme responsible for the catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphospate). This reaction is an important step in the biosynthesis of phospholipids and nucleic acids. Activity of this proten is important in the immune system, and loss of function of this gene has been associated with immunodeficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CTPS1 Gene-Disease associations (from GenCC):

severe combined immunodeficiency due to CTPS1 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

CTPS1 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=-0.59).

BP6

Variant 1-40988656-A-G is Benign according to our data. Variant chr1-40988656-A-G is described in ClinVar as Benign. ClinVar VariationId is 475187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.742 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTPS1	NM_001905.4 link	c.501A>G	p.Gln167Gln	synonymous_variant	Exon 5 of 19	ENST00000650070.2	NP_001896.2	P17812-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTPS1	ENST00000650070.2 link	c.501A>G	p.Gln167Gln	synonymous_variant	Exon 5 of 19		NM_001905.4	ENSP00000497602.1		P17812-1

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3354

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0361

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.0924

Gnomad SAS

AF:

0.0659

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00983

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0254

AC:

6387

AN:

251454

AF XY:

0.0269

show subpopulations

Gnomad AFR exome

AF:

0.0373

Gnomad AMR exome

AF:

0.00763

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.0979

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0167

AC:

24433

AN:

1461716

Hom.:

566

Cov.:

AF XY:

0.0183

AC XY:

13283

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0399

AC:

1334

AN:

33472

American (AMR)

AF:

0.00845

AC:

378

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

570

AN:

26120

East Asian (EAS)

AF:

0.0989

AC:

3926

AN:

39690

South Asian (SAS)

AF:

0.0659

AC:

5684

AN:

86232

European-Finnish (FIN)

AF:

0.00678

AC:

362

AN:

53418

Middle Eastern (MID)

AF:

0.0425

AC:

245

AN:

5768

European-Non Finnish (NFE)

AF:

0.00958

AC:

10654

AN:

1111902

Other (OTH)

AF:

0.0212

AC:

1280

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1075

2151

3226

4302

5377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.0220

AC:

3356

AN:

152286

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1729

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0359

AC:

1493

AN:

41554

American (AMR)

AF:

0.0117

AC:

179

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3470

East Asian (EAS)

AF:

0.0920

AC:

476

AN:

5174

South Asian (SAS)

AF:

0.0672

AC:

324

AN:

4822

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00983

AC:

669

AN:

68024

Other (OTH)

AF:

0.0265

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

159

318

478

637

796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0162

Hom.:

Bravo

AF:

0.0228

Asia WGS

AF:

0.0790

AC:

272

AN:

3478

EpiCase

AF:

0.0116

EpiControl

AF:

0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to CTPS1 deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.0

(source)

DANN

Benign

0.44

PhyloP100

0.74

PromoterAI

0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over