rs145092287

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001905.4(CTPS1):c.1692-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,611,348 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

CTPS1
NM_001905.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.27

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: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 1-41010160-G-C is Pathogenic according to our data. Variant chr1-41010160-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 140454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTPS1	NM_001905.4 link	c.1692-1G>C		splice_acceptor_variant, intron_variant	Intron 17 of 18	ENST00000650070.2	NP_001896.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTPS1	ENST00000650070.2 link	c.1692-1G>C		splice_acceptor_variant, intron_variant	Intron 17 of 18		NM_001905.4	ENSP00000497602.1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000957

AC:

AN:

250754

AF XY:

0.0000885

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000607

AC:

886

AN:

1459134

Hom.:

Cov.:

AF XY:

0.000625

AC XY:

454

AN XY:

726056

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000787

AC:

873

AN:

1109782

Other (OTH)

AF:

0.000182

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000145

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000339

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to CTPS1 deficiency

Pathogenic:5

Jul 12, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 17 of the CTPS1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs145092287, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with combined immunodeficiency (PMID: 24870241, 27638562, 32161190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140454). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24870241). For these reasons, this variant has been classified as Pathogenic. -

Jun 12, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 03, 2019

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Sep 16, 2022

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

DNA sequence analysis of the CTPS1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 17, c.1692-1G>C. This sequence change is predicted to affect normal splicing of the CTPS1 gene and result in an abnormal/unstable protein. This sequence change has been previously described in the homozygous state in multiple individuals with CTPS1-related combined immunodeficiency (PMIDs: 24870241, 27638562, 32161190) and is reported to be a founder mutation in the northwest England population. Experimental studies have shown that this sequence change is responsible for reduced protein expression and may result in unstable protein lacking the last exon (PMIDs: 24870241, 32161190). This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European subpopulation (dbSNP rs145092287). These collective evidences indicate that this sequence change is pathogenic. -

Mar 08, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24870241, 27638562, 34758253, 27543071, 31345272, 35983265, 32812031, 32161190) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.3

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.80

Position offset: 1

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