NM_002764.4:c.477C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.95

Publications

2 publications found

Variant links:

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

PRPS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPS1	NM_002764.4 link	c.477C>T	p.Ile159Ile	synonymous_variant	Exon 4 of 7	ENST00000372435.10	NP_002755.1
PRPS1	NM_001204402.2 link	c.-82-2740C>T		intron_variant	Intron 1 of 3		NP_001191331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10 link	c.477C>T	p.Ile159Ile	synonymous_variant	Exon 4 of 7	1	NM_002764.4	ENSP00000361512.4

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

690

AN:

111845

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00996

AC XY:

3619

AN XY:

363242

show subpopulations

African (AFR)

AF:

0.000833

AC:

AN:

26398

American (AMR)

AF:

0.00244

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00568

AC:

110

AN:

19382

East Asian (EAS)

AF:

0.0000331

AC:

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:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0104

AC:

8755

AN:

841795

Other (OTH)

AF:

0.00848

AC:

391

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

383

765

1148

1530

1913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00617

AC:

690

AN:

111897

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

174

AN XY:

34081

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

30868

American (AMR)

AF:

0.00191

AC:

AN:

10496

Ashkenazi Jewish (ASJ)

AF:

0.00642

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.0142

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

6029

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0101

AC:

537

AN:

53190

Other (OTH)

AF:

0.0111

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00663

Hom.:

Bravo

AF:

0.00555

EpiCase

AF:

0.0100

EpiControl

AF:

0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile159Ile in Exon 04 of PRPS1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.8% (42/5545) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs61752962). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hearing loss, X-linked 1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arts syndrome

Benign:2

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Phosphoribosylpyrophosphate synthetase superactivity

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease X-linked recessive 5

Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arts syndrome;C1839566:Charcot-Marie-Tooth disease X-linked recessive 5;C1844677:Hearing loss, X-linked 1;C1970827:Phosphoribosylpyrophosphate synthetase superactivity

Benign:1

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

8.5

(source)

DANN

Benign

0.74

PhyloP100

1.9

PromoterAI

0.010

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over