chrX-12791602-C-A

Position:

• chrX-12791602-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002765.5(PRPS2):​c.105C>A​(p.Phe35Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.17

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS2	NM_002765.5	c.105C>A	p.Phe35Leu	missense_variant	1/7	ENST00000380668.10	NP_002756.1
PRPS2	NM_001039091.3	c.105C>A	p.Phe35Leu	missense_variant	1/7		NP_001034180.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS2	ENST00000380668.10	c.105C>A	p.Phe35Leu	missense_variant	1/7	1	NM_002765.5	ENSP00000370043.5
PRPS2	ENST00000398491.6	c.105C>A	p.Phe35Leu	missense_variant	1/7	1		ENSP00000381504.2
PRPS2	ENST00000380663.7	c.105C>A	p.Phe35Leu	missense_variant	1/4	4		ENSP00000370038.3
PRPS2	ENST00000489404.5	c.105C>A	p.Phe35Leu	missense_variant	1/4	2		ENSP00000419380.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

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 23, 2023

The c.105C>A (p.F35L) alteration is located in exon 1 (coding exon 1) of the PRPS2 gene. This alteration results from a C to A substitution at nucleotide position 105, causing the phenylalanine (F) at amino acid position 35 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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	4.1	.;H;H;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.012, 0.022	.;B;B;.
Vest4		0.66, 0.65, 0.61
MutPred		0.55		Loss of catalytic residue at F35 (P = 0.0242);Loss of catalytic residue at F35 (P = 0.0242);Loss of catalytic residue at F35 (P = 0.0242);Loss of catalytic residue at F35 (P = 0.0242);
MVP		0.98
MPC		1.7
ClinPred		0.74	D
GERP RS		1.7
Varity_R		0.67
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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-12809721;