17-3689500-C-G

Position:

• chr17-3689500-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002561.4(P2RX5):​c.745G>C​(p.Ala249Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: P2RX5 NM_002561.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.74

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:49191): (P2RX5-TAX1BP3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring P2RX5 (purinergic receptor P2X, ligand-gated ion channel, 5) and TAX1BP3 (Tax1 binding protein 3) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

P2RX5-TAX1BP3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX5	NM_002561.4	c.745G>C	p.Ala249Pro	missense_variant	7/12	ENST00000225328.10	NP_002552.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX5	ENST00000225328.10	c.745G>C	p.Ala249Pro	missense_variant	7/12	1	NM_002561.4	ENSP00000225328.5
P2RX5	ENST00000697413.1	c.745G>C	p.Ala249Pro	missense_variant	7/13			ENSP00000513301.1
P2RX5-TAX1BP3	ENST00000550383.1	n.745G>C		non_coding_transcript_exon_variant	7/15	2		ENSP00000455681.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Dec 03, 2024

The c.745G>C (p.A249P) alteration is located in exon 7 (coding exon 7) of the P2RX5 gene. This alteration results from a G to C substitution at nucleotide position 745, causing the alanine (A) at amino acid position 249 to be replaced by a proline (P). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;.;T;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.5	.;.;.;H;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	.;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;D
Vest4		0.98
MutPred		0.90		.;.;.;Loss of stability (P = 0.0479);.;.;
MVP		0.61
MPC		0.69
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-3592794;