chrX-107628713-A-C

Variant names:

• chrX-107628713-A-C
• NM_002764.4:c.85A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002764.4(PRPS1):​c.85A>C​(p.Lys29Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K29K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PRPS1 NM_002764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.33
• Publications: 0 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

ENSG00000294392 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.85A>C	p.Lys29Gln	missense	Exon 1 of 7	NP_002755.1	P60891-1
	PRPS1	NM_001204402.2		c.-120A>C		5_prime_UTR	Exon 1 of 4	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.85A>C	p.Lys29Gln	missense	Exon 1 of 7	ENSP00000361512.4	P60891-1
	PRPS1	ENST00000643795.2		c.85A>C	p.Lys29Gln	missense	Exon 1 of 7	ENSP00000496286.1	A0A2R8Y7H4
	PRPS1	ENST00000372418.4	TSL:3	c.85A>C	p.Lys29Gln	missense	Exon 1 of 6	ENSP00000361495.2	B1ALA9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.9	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.52
Sift	Benign	0.098	T
Sift4G	Benign	0.15	T
Polyphen		0.26	B
Vest4		0.46
MutPred		0.44		Loss of methylation at K29 (P = 0.0574)
MVP		0.96
MPC		1.8
ClinPred		0.85	D
GERP RS		4.9
PromoterAI		0.10	Neutral
Varity_R		0.85
gMVP		0.91
Mutation Taster		=61/39	polymorphism

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

hg19: chrX-106871943;