rs137852540

Variant names:

• chrX-107640936-A-G
• rs137852540
• NM_002764.4:c.341A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_002764.4(PRPS1):​c.341A>G​(p.Asn114Ser) 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, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.84
• Publications: 17 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Charcot-Marie-Tooth disease X-linked recessive 5

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

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• phosphoribosylpyrophosphate synthetase superactivity

  Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002764.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant X-107640936-A-G is Pathogenic according to our data. Variant chrX-107640936-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	NM_002764.4	MANE Select	c.341A>G	p.Asn114Ser	missense	Exon 3 of 7	NP_002755.1	P60891-1
	PRPS1	NM_001204402.2		c.-82-4241A>G		intron	N/A	NP_001191331.1	B7ZB02

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	ENST00000372435.10	TSL:1 MANE Select	c.341A>G	p.Asn114Ser	missense	Exon 3 of 7	ENSP00000361512.4	P60891-1
	PRPS1	ENST00000643795.2		c.341A>G	p.Asn114Ser	missense	Exon 3 of 7	ENSP00000496286.1	A0A2R8Y7H4
	PRPS1	ENST00000372419.3	TSL:2	c.341A>G	p.Asn114Ser	missense	Exon 3 of 3	ENSP00000361496.3	B1ALA7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Arts syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Phosphoribosylpyrophosphate synthetase superactivity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		8.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.018	D
Polyphen		0.68	P
Vest4		0.66
MutPred		0.79		Loss of stability (P = 0.0479)
MVP		0.99
MPC		2.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.98
Mutation Taster		=6/94	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: rs137852540; hg19: chrX-106884166;