X-107639301-A-C

Position:

• chrX-107639301-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_002764.4(PRPS1):​c.129A>C​(p.Glu43Asp) variant causes a missense change. 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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.04

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 6 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, 0.841
• PP5: Variant X-107639301-A-C is Pathogenic according to our data. Variant chrX-107639301-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 9934.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-107639301-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPS1	NM_002764.4	c.129A>C	p.Glu43Asp	missense_variant	2/7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2	c.-82-5876A>C		intron_variant			NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10	c.129A>C	p.Glu43Asp	missense_variant	2/7	1	NM_002764.4	ENSP00000361512	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked recessive 5 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;.;.;N
REVEL	Uncertain	0.63
Sift	Benign	0.091	T;.;.;T
Sift4G	Benign	0.071	T;.;.;T
Polyphen		0.0020	B;.;.;.
Vest4		0.83
MutPred		0.79		Gain of catalytic residue at G45 (P = 0.1323);Gain of catalytic residue at G45 (P = 0.1323);Gain of catalytic residue at G45 (P = 0.1323);Gain of catalytic residue at G45 (P = 0.1323);
MVP		1.0
MPC		1.5
ClinPred		0.50	T
GERP RS		2.2
Varity_R		0.80
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

LitVar

Other links and lift over

dbSNP: rs80338731; hg19: chrX-106882531;