rs587781261

Positions:

• chrX-107640932-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_002764.4(PRPS1):​c.337G>T​(p.Ala113Ser) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.48

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 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002764.4
• 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, 0.953
• PP5: Variant X-107640932-G-T is Pathogenic according to our data. Variant chrX-107640932-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 140571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-107640932-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPS1	NM_002764.4	c.337G>T	p.Ala113Ser	missense_variant	3/7	ENST00000372435.10
PRPS1	NM_001204402.2	c.-82-4245G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPS1	ENST00000372435.10	c.337G>T	p.Ala113Ser	missense_variant	3/7	1	NM_002764.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing loss, X-linked 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2014	- -
Pathogenic, criteria provided, single submitter	research	Molecular Genetics and RNA Biology, University of Milan	Oct 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.011	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.81		Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs587781261; hg19: chrX-106884162;