rs61752962

chrX-107642437-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002764.4(PRPS1):c.477C>T(p.Ile159=) 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:16
• Conservation: PhyloP100: 1.95

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]

ACMG classification

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 GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPS1	NM_002764.4	c.477C>T	p.Ile159=	synonymous_variant	4/7	ENST00000372435.10
PRPS1	NM_001204402.2	c.-82-2740C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPS1	ENST00000372435.10	c.477C>T	p.Ile159=	synonymous_variant	4/7	1	NM_002764.4	P1

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 690 AN: 111845 Hom.: 3 Cov.: 23 AF XY: 0.00506 AC XY: 172 AN XY: 34019

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.: 7 AF XY: 0.00872 AC XY: 592 AN XY: 67919

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.: 42 Cov.: 30 AF XY: 0.00996 AC XY: 3619 AN XY: 363242

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.: 3 Cov.: 23 AF XY: 0.00511 AC XY: 174 AN XY: 34081

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.: 77

Bravo AF: 0.00555

EpiCase AF: 0.0100

EpiControl AF: 0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -

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

Invitae

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

Other links and lift over

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