1-40984895-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001905.4(CTPS1):c.241C>T(p.Arg81Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,605,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R81H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CTPS1 NM_001905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34468627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTPS1	NM_001905.4	c.241C>T	p.Arg81Cys	missense_variant	3/19	ENST00000650070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTPS1	ENST00000650070.2	c.241C>T	p.Arg81Cys	missense_variant	3/19		NM_001905.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248014 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1453030 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 722146

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000683

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000723

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency due to CTPS1 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals with CTPS1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 81 of the CTPS1 protein (p.Arg81Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;T;.;.;T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;M;.;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.1	N;.;.;.;.;.;N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D;.;.;.;.;.;D
Sift4G	Uncertain	0.029	D;.;.;.;.;.;D
Polyphen		0.21	B;B;.;B;.;.;B
Vest4		0.44
MutPred		0.41		Gain of methylation at K84 (P = 0.0807);Gain of methylation at K84 (P = 0.0807);Gain of methylation at K84 (P = 0.0807);Gain of methylation at K84 (P = 0.0807);Gain of methylation at K84 (P = 0.0807);Gain of methylation at K84 (P = 0.0807);Gain of methylation at K84 (P = 0.0807);
MVP		0.73
MPC		1.3
ClinPred		0.72	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.72

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: rs748131892; hg19: chr1-41450567;