rs867288458

Positions:

• chrX-107645287-G-A
• chrX-107645287-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The ENST00000372435.10(PRPS1):​c.641G>A​(p.Arg214Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,234 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: PRPS1 ENST00000372435.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.50

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-107645286-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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). GenCC has associacion of 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, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.641G>A	p.Arg214Gln	missense_variant	5/7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.29G>A	p.Arg10Gln	missense_variant	2/4		NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10	c.641G>A	p.Arg214Gln	missense_variant	5/7	1	NM_002764.4	ENSP00000361512	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098234 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363588

Gnomad4 AFR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 02, 2019

- -

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 20, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 214 of the PRPS1 protein (p.Arg214Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1320158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRPS1 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg214 amino acid residue in PRPS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28967191; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Arts syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Jun 21, 2023

It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg214Trp) has been reported as pathogenic/likely pathogenic (ClinVar ID: VCV000446163.5 PM5). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.696, 3Cnet: 0.610, PP3). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as a variant of uncertain significance according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;D;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.3	.;M;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	.;N;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.013	.;D;.;.
Sift4G	Uncertain	0.011	D;D;.;.
Polyphen		0.96	.;D;.;.
Vest4		0.66
MutPred		0.64		.;Loss of ubiquitination at K212 (P = 0.0877);Loss of ubiquitination at K212 (P = 0.0877);.;
MVP		0.98
MPC		2.4
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.60
gMVP		0.98

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: rs867288458; hg19: chrX-106888517; COSMIC: COSV65054268; COSMIC: COSV65054268;