12-121223039-C-T

Position:

• chr12-121223039-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002560.3(P2RX4):​c.520C>T​(p.Pro174Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: P2RX4 NM_002560.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.65

Genes affected

P2RX4 (HGNC:8535): (purinergic receptor P2X 4) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel with high calcium permeability. The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and PPADS. The product of this gene has the lowest sensitivity for these antagonists. Multiple alternatively spliced transcript variants, some protein-coding and some not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX4	NM_002560.3	c.520C>T	p.Pro174Ser	missense_variant	5/12	ENST00000337233.9	NP_002551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX4	ENST00000337233.9	c.520C>T	p.Pro174Ser	missense_variant	5/12	1	NM_002560.3	ENSP00000336607.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 07, 2023

The c.520C>T (p.P174S) alteration is located in exon 5 (coding exon 5) of the P2RX4 gene. This alteration results from a C to T substitution at nucleotide position 520, causing the proline (P) at amino acid position 174 to be replaced by a serine (S). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Benign	0.23
Sift	Benign	0.038	D;.;T
Sift4G	Benign	0.096	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.71
MutPred		0.55		Loss of glycosylation at T171 (P = 0.068);Loss of glycosylation at T171 (P = 0.068);.;
MVP		0.85
MPC		1.1
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.28
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs1457678965; hg19: chr12-121660842;