chr1-41001131-G-A

Variant names:

• chr1-41001131-G-A
• rs12718433
• NM_001905.4:c.1094+14G>A

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: -2.50
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001905.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS1	NM_001905.4	MANE Select	c.1094+14G>A		intron	N/A	NP_001896.2
	CTPS1	NM_001301237.2		c.626+14G>A		intron	N/A	NP_001288166.1
	CTPS1	NR_125440.2		n.1241+14G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS1	ENST00000650070.2	MANE Select	c.1094+14G>A		intron	N/A	ENSP00000497602.1
	CTPS1	ENST00000372616.1	TSL:2	c.1094+14G>A		intron	N/A	ENSP00000361699.1
	CTPS1	ENST00000470271.6	TSL:3	c.1094+14G>A		intron	N/A	ENSP00000497901.2

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

GnomAD2 exomes AF: 0.406 AC: 93307 AN: 229616 AF XY: 0.405

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 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

African (AFR) AF: 0.141 AC: 4512 AN: 32060

American (AMR) AF: 0.547 AC: 20408 AN: 37294

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 10177 AN: 25348

East Asian (EAS) AF: 0.423 AC: 16503 AN: 38998

South Asian (SAS) AF: 0.335 AC: 27245 AN: 81332

European-Finnish (FIN) AF: 0.418 AC: 22134 AN: 52942

Middle Eastern (MID) AF: 0.327 AC: 1859 AN: 5684

European-Non Finnish (NFE) AF: 0.425 AC: 466786 AN: 1099374

Other (OTH) AF: 0.404 AC: 23971 AN: 59312

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

African (AFR) AF: 0.161 AC: 6691 AN: 41464

American (AMR) AF: 0.501 AC: 7659 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 1395 AN: 3472

East Asian (EAS) AF: 0.415 AC: 2139 AN: 5158

South Asian (SAS) AF: 0.333 AC: 1603 AN: 4810

European-Finnish (FIN) AF: 0.425 AC: 4482 AN: 10542

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28196 AN: 67944

Other (OTH) AF: 0.375 AC: 790 AN: 2108

Alfa AF: 0.298 Hom.: 1526

Bravo AF: 0.353

Asia WGS AF: 0.335 AC: 1163 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Combined immunodeficiency due to CTPS1 deficiency (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.026
DANN	Benign	0.50
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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