11-57348664-A-C

Variant names:

• chr11-57348664-A-C
• rs1460276548
• NM_002559.5:c.523A>C

Variant summary

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

The NM_002559.5(P2RX3):​c.523A>C​(p.Ile175Leu) 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: P2RX3 NM_002559.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.15

Genes affected

P2RX3 (HGNC:8534): (purinergic receptor P2X 3) This gene encodes a member of the P2X purinergic receptor (purinoceptor) gene family which includes seven members (P2RX1 - P2RX7). P2X purinoceptors are a family of cation-permeable, ligand-gated ion channels that open in response to the binding of extracellular adenosine 5'-triphosphate (ATP). The encoded protein is a subunit of the trimeric P2X3 receptor ion channel which is expressed by sensory or autonomic neurons. A deficiency of the orthologous protein in mice is associated with reduced pain-related behavior and urinary bladder hyporeflexia. [provided by RefSeq, Aug 2017]

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, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX3	NM_002559.5	c.523A>C	p.Ile175Leu	missense_variant	Exon 6 of 12	ENST00000263314.3	NP_002550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX3	ENST00000263314.3	c.523A>C	p.Ile175Leu	missense_variant	Exon 6 of 12	1	NM_002559.5	ENSP00000263314.2
P2RX3	ENST00000534820.1	n.*125A>C		non_coding_transcript_exon_variant	Exon 3 of 5	3		ENSP00000434166.1
P2RX3	ENST00000534820.1	n.*125A>C		3_prime_UTR_variant	Exon 3 of 5	3		ENSP00000434166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.00068	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	.;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0090	.;D
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.73		Loss of ubiquitination at K176 (P = 0.0566);Loss of ubiquitination at K176 (P = 0.0566);
MVP		0.65
MPC		0.92
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.76
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1460276548; hg19: chr11-57116138;