rs80338732

Variant names:

• chrX-107640939-T-C
• rs80338732
• NM_002764.4:c.344T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_002764.4(PRPS1):​c.344T>C​(p.Met115Thr) 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: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.58

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 9 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, 0.977
• PP5: Variant X-107640939-T-C is Pathogenic according to our data. Variant chrX-107640939-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-107640939-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.344T>C	p.Met115Thr	missense_variant	Exon 3 of 7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.-82-4238T>C		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.344T>C	p.Met115Thr	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: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked recessive 5 Pathogenic:2 Other:1

Feb 28, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17701900, 33493137). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.89 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PRPS1 related disorder (ClinVar ID: VCV000009935 /PMID: 17701900).A different missense change at the same codon (p.Met115Val) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000140572 /PMID: 25182139). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Sep 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 115 of the PRPS1 protein (p.Met115Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5) (PMID: 17701900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9935). 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%. Experimental studies have shown that this missense change affects PRPS1 function (PMID: 17701900, 33493137). This variant disrupts the p.Met115 amino acid residue in PRPS1. Other variant(s) that disrupt this residue have been observed in individuals with PRPS1-related conditions (PMID: 25182139), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.97	D;.;.
Vest4		0.88
MutPred		0.88		Loss of ubiquitination at K110 (P = 0.1287);Loss of ubiquitination at K110 (P = 0.1287);Loss of ubiquitination at K110 (P = 0.1287);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.97
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: rs80338732; hg19: chrX-106884169;