NM_002561.4:c.1060G>C

Variant names:

• chr17-3681900-C-G
• rs147193130
• NM_002561.4:c.1060G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002561.4(P2RX5):​c.1060G>C​(p.Val354Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: P2RX5 NM_002561.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34686726).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002561.4. 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
	P2RX5	NM_002561.4	MANE Select	c.1060G>C	p.Val354Leu	missense	Exon 10 of 12	NP_002552.2
	P2RX5	NM_001204519.2		c.1057G>C	p.Val353Leu	missense	Exon 10 of 12	NP_001191448.1	Q93086-1
	P2RX5	NM_001204520.2		c.988G>C	p.Val330Leu	missense	Exon 9 of 11	NP_001191449.1	Q93086-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX5	ENST00000225328.10	TSL:1 MANE Select	c.1060G>C	p.Val354Leu	missense	Exon 10 of 12	ENSP00000225328.5	Q93086-3
	P2RX5	ENST00000697413.1		c.1126G>C	p.Val376Leu	missense	Exon 11 of 13	ENSP00000513301.1	Q93086-6
	P2RX5	ENST00000547178.5	TSL:1	c.1057G>C	p.Val353Leu	missense	Exon 10 of 12	ENSP00000448355.1	Q93086-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251092 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457882 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33382

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108498

Other (OTH) AF: 0.00 AC: 0 AN: 60256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.0000482 AC: 2 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Benign	0.060	T
Sift4G	Benign	0.084	T
Polyphen		0.18	B
Vest4		0.53
MutPred		0.65		Gain of ubiquitination at K349 (P = 0.0564)
MVP		0.31
MPC		0.17
ClinPred		0.16	T
GERP RS		3.7
Varity_R		0.22
gMVP		0.38

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

Other links and lift over

dbSNP: rs147193130; hg19: chr17-3585194;