rs587781263

Positions:

• chrX-107650000-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_002764.4(PRPS1):​c.925G>T​(p.Val309Phe) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

Genes affected

PRPS1 (HGNC:9462): (phosphoribosyl pyrophosphate synthetase 1) This gene encodes an enzyme that catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for purine metabolism and nucleotide biosynthesis. Defects in this gene are a cause of phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive type 5 and Arts Syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PRPS1. . Gene score misZ: 3.7321 (greater than the threshold 3.09). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. GenCC has associacion of the gene with severe phosphoribosylpyrophosphate synthetase superactivity, Arts syndrome, PRPS1 deficiency disorder, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, mild phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive 5, phosphoribosylpyrophosphate synthetase superactivity, X-linked nonsyndromic hearing loss, hearing loss, X-linked 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant X-107650000-G-T is Pathogenic according to our data. Variant chrX-107650000-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 140573.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-107650000-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.925G>T	p.Val309Phe	missense_variant	7/7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.313G>T	p.Val105Phe	missense_variant	4/4		NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10	c.925G>T	p.Val309Phe	missense_variant	7/7	1	NM_002764.4	ENSP00000361512.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked recessive 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2014	- -
Pathogenic, criteria provided, single submitter	research	Molecular Genetics and RNA Biology, University of Milan	Oct 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.4	.;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.96	.;D;.
Vest4		0.86
MutPred		0.55		.;Loss of phosphorylation at Y311 (P = 0.1661);.;
MVP		0.99
MPC		3.3
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.99
gMVP		0.99

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: rs587781263; hg19: chrX-106893230;