rs12718433

chr1-41001131-G-Achr1-41001131-G-Cchr1-41001131-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001905.4(CTPS1):c.1094+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,584,336 control chromosomes in the GnomAD database, including 136,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10655 hom., cov: 32)
  • Exomes 𝑓: 0.41 (125572 hom.)
• Consequence: CTPS1 NM_001905.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.50

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-41001131-G-A is Benign according to our data. Variant chr1-41001131-G-A is described in ClinVar as [Benign]. Clinvar id is 402571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTPS1	NM_001905.4	c.1094+14G>A		intron_variant		ENST00000650070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTPS1	ENST00000650070.2	c.1094+14G>A		intron_variant			NM_001905.4	P1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53344 AN: 151874 Hom.: 10653 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.406 AC: 93307 AN: 229616 Hom.: 19733 AF XY: 0.405 AC XY: 50628 AN XY: 124906

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.406

Gnomad SAS exome AF: 0.332

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.420

Gnomad OTH exome AF: 0.426

GnomAD4 exome AF: 0.414 AC: 593595 AN: 1432344 Hom.: 125572 Cov.: 27 AF XY: 0.412 AC XY: 293394 AN XY: 712958

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.425

Gnomad4 OTH exome AF: 0.404

GnomAD4 genome AF: 0.351 AC: 53353 AN: 151992 Hom.: 10655 Cov.: 32 AF XY: 0.356 AC XY: 26466 AN XY: 74272

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.402

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.425

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.375

Alfa AF: 0.302 Hom.: 1516

Bravo AF: 0.353

Asia WGS AF: 0.335 AC: 1163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 70. Only high quality variants are reported. -

Severe combined immunodeficiency due to CTPS1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.026
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs12718433; hg19: chr1-41466803; COSMIC: COSV65452294; COSMIC: COSV65452294;