NM_002764.4:c.193G>A

Variant names:

• chrX-107639365-G-A
• rs180177151
• NM_002764.4:c.193G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002764.4(PRPS1):​c.193G>A​(p.Asp65Asn) 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 (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: 9.35
• Publications: 12 publications found

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]

PRPS1 Gene-Disease associations (from GenCC):

• Arts syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Charcot-Marie-Tooth disease X-linked recessive 5

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P
• hearing loss, X-linked 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• PRPS1 deficiency disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• mild phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant X-107639365-G-A is Pathogenic according to our data. Variant chrX-107639365-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9938.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002764.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	NM_002764.4	MANE Select	c.193G>A	p.Asp65Asn	missense	Exon 2 of 7	NP_002755.1
	PRPS1	NM_001204402.2		c.-82-5812G>A		intron	N/A	NP_001191331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	ENST00000372435.10	TSL:1 MANE Select	c.193G>A	p.Asp65Asn	missense	Exon 2 of 7	ENSP00000361512.4
	PRPS1	ENST00000643795.2		c.193G>A	p.Asp65Asn	missense	Exon 2 of 7	ENSP00000496286.1
	PRPS1	ENST00000372418.4	TSL:3	c.193G>A	p.Asp65Asn	missense	Exon 2 of 6	ENSP00000361495.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hearing loss, X-linked 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.62
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.18	B
Vest4		0.72
MutPred		0.83		Gain of helix (P = 0.132)
MVP		0.94
MPC		1.8
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.90
gMVP		0.99
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs180177151; hg19: chrX-106882595;