rs1556300610

chrX-107645232-C-T

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.586C>T(p.Arg196Trp) variant causes a missense change involving the alteration of a non-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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.15

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 where missense usually causes diseases, PRPS1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant X-107645232-C-T is Pathogenic according to our data. Variant chrX-107645232-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-107645232-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPS1	NM_002764.4	c.586C>T	p.Arg196Trp	missense_variant	5/7	ENST00000372435.10
PRPS1	NM_001204402.2	c.-27C>T		5_prime_UTR_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPS1	ENST00000372435.10	c.586C>T	p.Arg196Trp	missense_variant	5/7	1	NM_002764.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 446162). This missense change has been observed in individuals with clinical features of PRPS1-related conditions (PMID: 24961627, 28967191, 32781272; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 196 of the PRPS1 protein (p.Arg196Trp). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28967191, 24961627, 32650483, 32781272) -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Hardcastle Lab, UCL Institute of Ophthalmology

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.4	D;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		0.62	P;.;.
Vest4		0.89
MutPred		0.72		Loss of disorder (P = 0.0321);Loss of disorder (P = 0.0321);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
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: rs1556300610; hg19: chrX-106888462; COSMIC: COSV104423748; COSMIC: COSV104423748;