X-12820744-G-A

Position:

• chrX-12820744-G-A

Variant summary

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

The NM_002765.5(PRPS2):​c.805G>A​(p.Val269Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,098,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: PRPS2 NM_002765.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38592356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS2	NM_002765.5	c.805G>A	p.Val269Ile	missense_variant	6/7	ENST00000380668.10	NP_002756.1
PRPS2	NM_001039091.3	c.814G>A	p.Val272Ile	missense_variant	6/7		NP_001034180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS2	ENST00000380668.10	c.805G>A	p.Val269Ile	missense_variant	6/7	1	NM_002765.5	ENSP00000370043.5
PRPS2	ENST00000398491.6	c.814G>A	p.Val272Ile	missense_variant	6/7	1		ENSP00000381504.2
PRPS2	ENST00000461630.1	c.370G>A	p.Val124Ile	missense_variant	4/5	1		ENSP00000418911.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098046 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363404

Gnomad4 AFR exome AF: 0.000152

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

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

May 14, 2024

The c.814G>A (p.V272I) alteration is located in exon 6 (coding exon 6) of the PRPS2 gene. This alteration results from a G to A substitution at nucleotide position 814, causing the valine (V) at amino acid position 272 to be replaced by an isoleucine (I). 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	Benign	0.13
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.60	N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.34
MutPred		0.51		Gain of catalytic residue at V270 (P = 0.1051);.;.;
MVP		0.77
MPC		1.2
ClinPred		0.83	D
GERP RS		4.9
Varity_R		0.29
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: rs1783587533; hg19: chrX-12838863;