X-107628649-C-A

Position:

• chrX-107628649-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002764.4(PRPS1):​c.21C>A​(p.Phe7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPS1	NM_002764.4	c.21C>A	p.Phe7Leu	missense_variant	1/7	ENST00000372435.10
PRPS1	NM_001204402.2	c.-184C>A		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPS1	ENST00000372435.10	c.21C>A	p.Phe7Leu	missense_variant	1/7	1	NM_002764.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.73	D;.;.;.;D
FATHMM_MKL	Benign	0.52	D
LIST_S2	Pathogenic	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.65	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	N;.;.;.;N
REVEL	Pathogenic	0.72
Sift	Benign	0.54	T;.;.;.;T
Sift4G	Benign	0.34	T;.;.;.;T
Polyphen		0.64	P;.;.;.;.
Vest4		0.77
MutPred		0.53		Loss of ubiquitination at K5 (P = 0.0656);Loss of ubiquitination at K5 (P = 0.0656);Loss of ubiquitination at K5 (P = 0.0656);Loss of ubiquitination at K5 (P = 0.0656);Loss of ubiquitination at K5 (P = 0.0656);
MVP		1.0
MPC		1.9
ClinPred		0.70	D
GERP RS		3.1
Varity_R		0.57
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-106871879;