chrX-107628673-A-C

Variant names:

• chrX-107628673-A-C
• NM_002764.4:c.45A>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002764.4(PRPS1):​c.45A>C​(p.Leu15Phe) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.879

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 Uncertain_significance. Variant got 5 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, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.45A>C	p.Leu15Phe	missense_variant	Exon 1 of 7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.-160A>C		5_prime_UTR_variant	Exon 1 of 4		NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10	c.45A>C	p.Leu15Phe	missense_variant	Exon 1 of 7	1	NM_002764.4	ENSP00000361512.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 15 of the PRPS1 protein (p.Leu15Phe). 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. 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%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;D
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.1	D;.;.;.;D
REVEL	Pathogenic	0.81
Sift	Benign	0.050	D;.;.;.;D
Sift4G	Benign	0.069	T;.;.;.;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.66
MutPred		0.65		Loss of ubiquitination at K18 (P = 0.1465);Loss of ubiquitination at K18 (P = 0.1465);Loss of ubiquitination at K18 (P = 0.1465);Loss of ubiquitination at K18 (P = 0.1465);Loss of ubiquitination at K18 (P = 0.1465);
MVP		1.0
MPC		2.3
ClinPred		0.99	D
GERP RS		-1.4
Varity_R		0.82
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-106871903;