rs61752962

Variant names:

• chrX-107642437-C-T
• rs61752962
• NM_002764.4:c.477C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002764.4(PRPS1):​c.477C>T​(p.Ile159Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,209,773 control chromosomes in the GnomAD database, including 45 homozygotes. There are 3,793 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., 174 hem., cov: 23)
  • Exomes 𝑓: 0.0095 (42 hom. 3619 hem.)
• Consequence: PRPS1 NM_002764.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.95
• Publications: 2 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant X-107642437-C-T is Benign according to our data. Variant chrX-107642437-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

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.477C>T	p.Ile159Ile	synonymous	Exon 4 of 7	NP_002755.1	P60891-1
	PRPS1	NM_001204402.2		c.-82-2740C>T		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.477C>T	p.Ile159Ile	synonymous	Exon 4 of 7	ENSP00000361512.4	P60891-1
	PRPS1	ENST00000643795.2		c.477C>T	p.Ile159Ile	synonymous	Exon 4 of 7	ENSP00000496286.1	A0A2R8Y7H4
	PRPS1	ENST00000372418.4	TSL:3	c.378C>T	p.Ile126Ile	synonymous	Exon 3 of 6	ENSP00000361495.2	B1ALA9

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 690 AN: 111845 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00642

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0138

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0113

GnomAD2 exomes AF: 0.00746 AC: 1368 AN: 183465 AF XY: 0.00872

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00281

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.00949 AC: 10417 AN: 1097876 Hom.: 42 Cov.: 30 AF XY: 0.00996 AC XY: 3619 AN XY: 363242

African (AFR) AF: 0.000833 AC: 22 AN: 26398

American (AMR) AF: 0.00244 AC: 86 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00568 AC: 110 AN: 19382

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30199

South Asian (SAS) AF: 0.0156 AC: 843 AN: 54143

European-Finnish (FIN) AF: 0.00358 AC: 145 AN: 40530

Middle Eastern (MID) AF: 0.0155 AC: 64 AN: 4135

European-Non Finnish (NFE) AF: 0.0104 AC: 8755 AN: 841795

Other (OTH) AF: 0.00848 AC: 391 AN: 46091

GnomAD4 genome AF: 0.00617 AC: 690 AN: 111897 Hom.: 3 Cov.: 23 AF XY: 0.00511 AC XY: 174 AN XY: 34081

African (AFR) AF: 0.00126 AC: 39 AN: 30868

American (AMR) AF: 0.00191 AC: 20 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00642 AC: 17 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.0142 AC: 38 AN: 2670

European-Finnish (FIN) AF: 0.00348 AC: 21 AN: 6029

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0101 AC: 537 AN: 53190

Other (OTH) AF: 0.0111 AC: 17 AN: 1528

Alfa AF: 0.00663 Hom.: 77

Bravo AF: 0.00555

EpiCase AF: 0.0100

EpiControl AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Arts syndrome (2)
-	-	2	Hearing loss, X-linked 1 (2)
-	-	2	Phosphoribosylpyrophosphate synthetase superactivity (2)
-	-	1	Arts syndrome;C1839566:Charcot-Marie-Tooth disease X-linked recessive 5;C1844677:Hearing loss, X-linked 1;C1970827:Phosphoribosylpyrophosphate synthetase superactivity (1)
-	-	1	Charcot-Marie-Tooth disease X-linked recessive 5 (1)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.5
DANN	Benign	0.74
PhyloP100		1.9
PromoterAI		0.010	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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: rs61752962; hg19: chrX-106885667; COSMIC: COSV65054155; COSMIC: COSV65054155;