rs180177152

Variant names:

• chrX-107639431-G-A
• rs180177152
• NM_002764.4:c.259G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002764.4(PRPS1):​c.259G>A​(p.Ala87Thr) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A87V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 9.45
• Publications: 14 publications found

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]

PRPS1 Gene-Disease associations (from GenCC):

• Arts syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Charcot-Marie-Tooth disease X-linked recessive 5

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• hearing loss, X-linked 1

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• PRPS1 deficiency disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• mild phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002764.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	NM_002764.4	MANE Select	c.259G>A	p.Ala87Thr	missense	Exon 2 of 7	NP_002755.1	P60891-1
	PRPS1	NM_001204402.2		c.-82-5746G>A		intron	N/A	NP_001191331.1	B7ZB02

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	ENST00000372435.10	TSL:1 MANE Select	c.259G>A	p.Ala87Thr	missense	Exon 2 of 7	ENSP00000361512.4	P60891-1
	PRPS1	ENST00000643795.2		c.259G>A	p.Ala87Thr	missense	Exon 2 of 7	ENSP00000496286.1	A0A2R8Y7H4
	PRPS1	ENST00000372418.4	TSL:3	c.259G>A	p.Ala87Thr	missense	Exon 2 of 6	ENSP00000361495.2	B1ALA9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth Neuropathy X (1)
1	-	-	Hearing loss, X-linked 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.85		Gain of phosphorylation at A87 (P = 0.0618)
MVP		1.0
MPC		1.9
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs180177152; hg19: chrX-106882661; COSMIC: COSV65054574;