1-40983388-A-T

Variant names:

• chr1-40983388-A-T
• rs1288200124
• NM_001905.4:c.98A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001905.4(CTPS1):​c.98A>T​(p.His33Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. H33R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CTPS1 NM_001905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41
• Publications: 0 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):

• combined immunodeficiency due to CTPS1 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38478073).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS1	NM_001905.4	MANE Select	c.98A>T	p.His33Leu	missense	Exon 2 of 19	NP_001896.2	P17812-1
	CTPS1	NR_125440.2		n.245A>T		non_coding_transcript_exon	Exon 2 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS1	ENST00000650070.2	MANE Select	c.98A>T	p.His33Leu	missense	Exon 2 of 19	ENSP00000497602.1	P17812-1
	CTPS1	ENST00000372616.1	TSL:2	c.98A>T	p.His33Leu	missense	Exon 1 of 18	ENSP00000361699.1	P17812-1
	CTPS1	ENST00000470271.6	TSL:3	c.98A>T	p.His33Leu	missense	Exon 2 of 19	ENSP00000497901.2	P17812-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461754 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined immunodeficiency due to CTPS1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		0.17	B
Vest4		0.53
MutPred		0.49		Gain of ubiquitination at K28 (P = 0.1062)
MVP		0.41
MPC		1.2
ClinPred		0.89	D
GERP RS		4.6
PromoterAI		-0.0084	Neutral
Varity_R		0.66
gMVP		0.84
Mutation Taster		=58/42	polymorphism

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: rs1288200124; hg19: chr1-41449060;