X-12820693-A-C

Position:

• chrX-12820693-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002765.5(PRPS2):​c.754A>C​(p.Ile252Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS2 NM_002765.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.76

Genes affected

PRPS2 (HGNC:9465): (phosphoribosyl pyrophosphate synthetase 2) This gene encodes a phosphoribosyl pyrophosphate synthetase that plays a central role in the synthesis of purines and pyrimidines. The encoded protein catalyzes the synthesis of 5-phosphoribosyl 1-pyrophosphate from ATP and D-ribose 5-phosphate. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS2	NM_002765.5	c.754A>C	p.Ile252Leu	missense_variant	6/7	ENST00000380668.10	NP_002756.1
PRPS2	NM_001039091.3	c.763A>C	p.Ile255Leu	missense_variant	6/7		NP_001034180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS2	ENST00000380668.10	c.754A>C	p.Ile252Leu	missense_variant	6/7	1	NM_002765.5	ENSP00000370043.5
PRPS2	ENST00000398491.6	c.763A>C	p.Ile255Leu	missense_variant	6/7	1		ENSP00000381504.2
PRPS2	ENST00000461630.1	c.319A>C	p.Ile107Leu	missense_variant	4/5	1		ENSP00000418911.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.763A>C (p.I255L) alteration is located in exon 6 (coding exon 6) of the PRPS2 gene. This alteration results from a A to C substitution at nucleotide position 763, causing the isoleucine (I) at amino acid position 255 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.024	D
MutationAssessor	Benign	0.93	L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.15	T;T;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.73
MutPred		0.59		Gain of catalytic residue at I252 (P = 0.0446);.;.;
MVP		1.0
MPC		1.4
ClinPred		0.83	D
GERP RS		4.9
Varity_R		0.69
gMVP		0.86

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.

Other links and lift over

hg19: chrX-12838812;