chrX-107649991-G-A

Position:

• chrX-107649991-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_002764.4(PRPS1):​c.916G>A​(p.Gly306Arg) 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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 9.32

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 8 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, 0.94
• PP5: Variant X-107649991-G-A is Pathogenic according to our data. Variant chrX-107649991-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9940.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-107649991-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.916G>A	p.Gly306Arg	missense_variant	7/7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.304G>A	p.Gly102Arg	missense_variant	4/4		NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10	c.916G>A	p.Gly306Arg	missense_variant	7/7	1	NM_002764.4	ENSP00000361512.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hearing loss, X-linked 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

PRPS1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2024

The PRPS1 c.916G>A variant is predicted to result in the amino acid substitution p.Gly306Arg. This variant was reported to cause nonsyndromic sensorineural deafness in a single family with five affected males and two obligate carrier females with less severe hearing loss (Liu et al. 2010. PubMed ID: 20021999; Manolis et al. 1999. PubMed ID: 10503584). This variant was found to segregate with disease in a family with hearing loss (Internal Data, PreventionGenetics). An alternate nucleotide change affecting the same amino acid (p.Gly306Glu), has been reported to segregate with hearing loss in a family with four affected males and three unaffected female carriers (Gandía et al. 2015. PubMed ID: 25785835). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.2	.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.73
MutPred		0.77		.;Gain of solvent accessibility (P = 0.0306);.;
MVP		1.0
MPC		3.3
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.90

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: rs180177154; hg19: chrX-106893221;