rs587781262

Variant names:

• chrX-107640938-A-G
• rs587781262
• NM_002764.4:c.343A>G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_002764.4(PRPS1):​c.343A>G​(p.Met115Val) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.84

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PRPS1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 3.7321 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.918
• PP5: Variant X-107640938-A-G is Pathogenic according to our data. Variant chrX-107640938-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-107640938-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.343A>G	p.Met115Val	missense_variant	Exon 3 of 7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.-82-4239A>G		intron_variant	Intron 1 of 3		NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10	c.343A>G	p.Met115Val	missense_variant	Exon 3 of 7	1	NM_002764.4	ENSP00000361512.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 03, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 01, 2013

Molecular Genetics and RNA Biology, University of Milan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hearing loss, X-linked 1 Pathogenic:1

Oct 01, 2013

Molecular Genetics and RNA Biology, University of Milan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Mar 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest M115V depletes enzyme activity in a dose dependent manner (PMID: 25182139); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25182139, 26089585, 34803094) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		0.50	P;.;.
Vest4		0.84
MutPred		0.68		Gain of methylation at K110 (P = 0.1193);Gain of methylation at K110 (P = 0.1193);Gain of methylation at K110 (P = 0.1193);
MVP		1.0
MPC		2.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.94
gMVP		1.0

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: rs587781262; hg19: chrX-106884168;