chrX-107628581-T-TGCA

Variant names:

• chrX-107628581-T-TGCA
• rs1556297570
• NM_002764.4:c.-42_-40dupAGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_002764.4(PRPS1):​c.-42_-40dupAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,086 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: PRPS1 NM_002764.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.853
• Publications: 0 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

ENSG00000294392 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-107628581-T-TGCA is Benign according to our data. Variant chrX-107628581-T-TGCA is described in ClinVar as Likely_benign. ClinVar VariationId is 421764.Status of the report is criteria_provided_single_submitter, 1 stars.

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.-42_-40dupAGC		5_prime_UTR	Exon 1 of 7	NP_002755.1	P60891-1
	PRPS1	NM_001204402.2		c.-246_-244dupAGC		5_prime_UTR	Exon 1 of 4	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.-42_-40dupAGC		5_prime_UTR	Exon 1 of 7	ENSP00000361512.4	P60891-1
	PRPS1	ENST00000643795.2		c.-42_-40dupAGC		5_prime_UTR	Exon 1 of 7	ENSP00000496286.1	A0A2R8Y7H4
	PRPS1	ENST00000372418.4	TSL:3	c.-42_-40dupAGC		5_prime_UTR	Exon 1 of 6	ENSP00000361495.2	B1ALA9

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112086 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112086 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34236

African (AFR) AF: 0.0000324 AC: 1 AN: 30872

American (AMR) AF: 0.00 AC: 0 AN: 10569

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2711

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53204

Other (OTH) AF: 0.00 AC: 0 AN: 1492

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556297570; hg19: chrX-106871811;