Genetic Variant NM_175859.3:c.1342A>T (chrX-16639198-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_175859.3(CTPS2):c.1342A>T(p.Met448Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,489 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.54

Variant links:

Genes affected

CTPS2 (HGNC:2520): (CTP synthase 2) The protein encoded by this gene catalyzes the formation of CTP from UTP with the concomitant deamination of glutamine to glutamate. This protein is the rate-limiting enzyme in the synthesis of cytosine nucleotides, which play an important role in various metabolic processes and provide the precursors necessary for the synthesis of RNA and DNA. Cancer cells that exhibit increased cell proliferation also exhibit an increased activity of this encoded protein. Thus, this protein is an attractive target for selective chemotherapy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

CTPS2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTPS2	NM_175859.3 link	c.1342A>T	p.Met448Leu	missense_variant	Exon 14 of 19	ENST00000359276.9	NP_787055.1	Q9NRF8A0A024RC00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTPS2	ENST00000359276.9 link	c.1342A>T	p.Met448Leu	missense_variant	Exon 14 of 19	1	NM_175859.3	ENSP00000352222.4	Q9NRF8
CTPS2	ENST00000380241.7 link	c.1342A>T	p.Met448Leu	missense_variant	Exon 14 of 19	1		ENSP00000369590.3	Q9NRF8
CTPS2	ENST00000443824.5 link	c.1342A>T	p.Met448Leu	missense_variant	Exon 14 of 19	2		ENSP00000401264.1	Q9NRF8
CTPS2	ENST00000455276.1 link	c.205A>T	p.Met69Leu	missense_variant	Exon 4 of 5	5		ENSP00000400431.1	H0Y5S6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096489

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361877

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

D;D;D

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;.;.

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.7

M;M;M

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

D;D;D

Sift4G

Benign

0.067

T;T;T

Polyphen

0.62

P;P;P

Vest4

0.54

MutPred

0.84

Loss of MoRF binding (P = 0.0891);Loss of MoRF binding (P = 0.0891);Loss of MoRF binding (P = 0.0891);

MVP

0.54

MPC

1.4

ClinPred

0.94

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over