rs137852541

Positions:

• chrX-107645193-G-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.547G>C​(p.Asp183His) 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, 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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.959
• PP5: Variant X-107645193-G-C is Pathogenic according to our data. Variant chrX-107645193-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9929.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-107645193-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPS1	NM_002764.4	c.547G>C	p.Asp183His	missense_variant	5/7	ENST00000372435.10
PRPS1	NM_001204402.2	c.-66G>C		5_prime_UTR_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPS1	ENST00000372435.10	c.547G>C	p.Asp183His	missense_variant	5/7	1	NM_002764.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Arts syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 22, 2022

- -

Phosphoribosylpyrophosphate synthetase superactivity Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Nov 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.5	D;.;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.026	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.79		Gain of MoRF binding (P = 0.0411);Gain of MoRF binding (P = 0.0411);.;
MVP		1.0
MPC		3.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137852541; hg19: chrX-106888423;