17-3690428-C-G

Position:

• chr17-3690428-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002561.4(P2RX5):​c.532G>C​(p.Glu178Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: P2RX5 NM_002561.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002197
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.264

Genes affected

P2RX5 (HGNC:8536): (purinergic receptor P2X 5) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream gene, TAX1BP3 (Tax1 binding protein 3). [provided by RefSeq, Mar 2011]

P2RX5-TAX1BP3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105689645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RX5	NM_002561.4	c.532G>C	p.Glu178Gln	missense_variant, splice_region_variant	5/12	ENST00000225328.10
P2RX5-TAX1BP3	NR_037928.1	n.931G>C		splice_region_variant, non_coding_transcript_exon_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RX5	ENST00000225328.10	c.532G>C	p.Glu178Gln	missense_variant, splice_region_variant	5/12	1	NM_002561.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1455724 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4 AN XY: 724026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000992

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.532G>C (p.E178Q) alteration is located in exon 5 (coding exon 5) of the P2RX5 gene. This alteration results from a G to C substitution at nucleotide position 532, causing the glutamic acid (E) at amino acid position 178 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.99
DANN	Benign	0.36
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.27	T;T;T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.52	T;T;T;T;T;T
Polyphen		0.0040, 0.42	.;B;B;B;.;B
Vest4		0.12
MutPred		0.42		Loss of glycosylation at P177 (P = 0.0654);.;Loss of glycosylation at P177 (P = 0.0654);Loss of glycosylation at P177 (P = 0.0654);.;.;
MVP		0.27
MPC		0.13
ClinPred		0.23	T
GERP RS		-7.1
Varity_R		0.050
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.016
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: rs2050579370; hg19: chr17-3593722;