rs80338730

Variant names:

• chrX-107642407-G-A
• rs80338730
• NM_002764.4:c.447G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-107642407-G-A
• chrX-107642407-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002764.4(PRPS1):​c.447G>A​(p.Pro149Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 1,209,966 control chromosomes in the GnomAD database, including 3 homozygotes. There are 190 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P149P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (2 hom., 34 hem., cov: 23)
  • Exomes 𝑓: 0.00044 (1 hom. 156 hem.)
• Consequence: PRPS1 NM_002764.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.653
• Publications: 1 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: 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant X-107642407-G-A is Benign according to our data. Variant chrX-107642407-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.653 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000919 (103/112063) while in subpopulation EAS AF = 0.0266 (95/3574). AF 95% confidence interval is 0.0223. There are 2 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	NM_002764.4	MANE Select	c.447G>A	p.Pro149Pro	synonymous	Exon 4 of 7	NP_002755.1
	PRPS1	NM_001204402.2		c.-82-2770G>A		intron	N/A	NP_001191331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPS1	ENST00000372435.10	TSL:1 MANE Select	c.447G>A	p.Pro149Pro	synonymous	Exon 4 of 7	ENSP00000361512.4
	PRPS1	ENST00000643795.2		c.447G>A	p.Pro149Pro	synonymous	Exon 4 of 7	ENSP00000496286.1
	PRPS1	ENST00000372418.4	TSL:3	c.348G>A	p.Pro116Pro	synonymous	Exon 3 of 6	ENSP00000361495.2

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 103 AN: 112009 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0265

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00176 AC: 322 AN: 183471 AF XY: 0.00160

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.0226

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000435 AC: 478 AN: 1097903 Hom.: 1 Cov.: 30 AF XY: 0.000429 AC XY: 156 AN XY: 363275

African (AFR) AF: 0.0000758 AC: 2 AN: 26394

American (AMR) AF: 0.000170 AC: 6 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19379

East Asian (EAS) AF: 0.0139 AC: 419 AN: 30197

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 841847

Other (OTH) AF: 0.000586 AC: 27 AN: 46083

GnomAD4 genome AF: 0.000919 AC: 103 AN: 112063 Hom.: 2 Cov.: 23 AF XY: 0.000993 AC XY: 34 AN XY: 34251

African (AFR) AF: 0.000129 AC: 4 AN: 30931

American (AMR) AF: 0.000285 AC: 3 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.0266 AC: 95 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53190

Other (OTH) AF: 0.00 AC: 0 AN: 1531

Alfa AF: 0.000347 Hom.: 4

Bravo AF: 0.000782

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Arts syndrome (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 Neuropathy X (1)
-	-	1	Hearing loss, X-linked 1 (1)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	not provided (1)
-	-	1	Phosphoribosylpyrophosphate synthetase superactivity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.6
DANN	Benign	0.57
PhyloP100		0.65
PromoterAI		0.0092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs80338730; hg19: chrX-106885637; COSMIC: COSV100978879; COSMIC: COSV100978879;