chrX-107642416-A-G

Variant names:

• chrX-107642416-A-G
• rs61735617
• NM_002764.4:c.456A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002764.4(PRPS1):​c.456A>G​(p.Leu152Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,209,968 control chromosomes in the GnomAD database, including 14 homozygotes. There are 477 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. L152L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., 230 hem., cov: 23)
  • Exomes 𝑓: 0.00086 (6 hom. 247 hem.)
• Consequence: PRPS1 NM_002764.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.147
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-107642416-A-G is Benign according to our data. Variant chrX-107642416-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.147 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00737 (826/112048) while in subpopulation AFR AF = 0.0249 (770/30891). AF 95% confidence interval is 0.0235. There are 8 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.456A>G	p.Leu152Leu	synonymous	Exon 4 of 7	NP_002755.1	P60891-1
	PRPS1	NM_001204402.2		c.-82-2761A>G		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.456A>G	p.Leu152Leu	synonymous	Exon 4 of 7	ENSP00000361512.4	P60891-1
	PRPS1	ENST00000643795.2		c.456A>G	p.Leu152Leu	synonymous	Exon 4 of 7	ENSP00000496286.1	A0A2R8Y7H4
	PRPS1	ENST00000372418.4	TSL:3	c.357A>G	p.Leu119Leu	synonymous	Exon 3 of 6	ENSP00000361495.2	B1ALA9

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 825 AN: 111995 Hom.: 8 Cov.: 23

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.0126

GnomAD2 exomes AF: 0.00238 AC: 436 AN: 183474 AF XY: 0.00169

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000855

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000862 AC: 946 AN: 1097920 Hom.: 6 Cov.: 30 AF XY: 0.000680 AC XY: 247 AN XY: 363284

African (AFR) AF: 0.0286 AC: 754 AN: 26396

American (AMR) AF: 0.00190 AC: 67 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4136

European-Non Finnish (NFE) AF: 0.0000344 AC: 29 AN: 841859

Other (OTH) AF: 0.00195 AC: 90 AN: 46085

GnomAD4 genome AF: 0.00737 AC: 826 AN: 112048 Hom.: 8 Cov.: 23 AF XY: 0.00672 AC XY: 230 AN XY: 34250

African (AFR) AF: 0.0249 AC: 770 AN: 30891

American (AMR) AF: 0.00333 AC: 35 AN: 10515

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53227

Other (OTH) AF: 0.0124 AC: 19 AN: 1531

Alfa AF: 0.000305 Hom.: 0

Bravo AF: 0.00858

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Arts syndrome (1)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	Hearing loss, X-linked 1 (1)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Phosphoribosylpyrophosphate synthetase superactivity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		0.15
PromoterAI		0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61735617; hg19: chrX-106885646;