rs61752962

Positions:

chrX-107642437-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 94083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-107642437-C-T is described in Lovd as [Likely_benign]. Variant chrX-107642437-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PRPS1	NM_002764.4 link	c.477C>T	p.Ile159Ile	synonymous_variant	4/7	ENST00000372435.10	NP_002755.1	P60891-1
PRPS1	NM_001204402.2 link	c.-82-2740C>T		intron_variant			NP_001191331.1	P60891B7ZB02

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPS1	ENST00000372435.10 link	c.477C>T	p.Ile159Ile	synonymous_variant	4/7	1	NM_002764.4	ENSP00000361512.4		P60891-1

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

690

AN:

111845

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

172

AN XY:

34019

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

GnomAD3 exomes

AF:

0.00746

AC:

1368

AN:

183465

Hom.:

AF XY:

0.00872

AC XY:

592

AN XY:

67919

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 SAS exome

AF:

0.0147

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

Gnomad4 AFR exome

AF:

0.000833

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00568

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0156

Gnomad4 FIN exome

AF:

0.00358

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00848

GnomAD4 genome

AF:

0.00617

AC:

690

AN:

111897

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

174

AN XY:

34081

show subpopulations

Gnomad4 AFR

AF:

0.00126

Gnomad4 AMR

AF:

0.00191

Gnomad4 ASJ

AF:

0.00642

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0142

Gnomad4 FIN

AF:

0.00348

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.0111

Alfa

AF:

0.00895

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hearing loss, X-linked 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Arts syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Phosphoribosylpyrophosphate synthetase superactivity

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Charcot-Marie-Tooth Neuropathy X

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Charcot-Marie-Tooth disease X-linked recessive 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

8.5

DANN

Benign

0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over