Genetic Variant NM_002560.3:c.944A>G (chr12-121232473-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002560.3(P2RX4):c.944A>G(p.Tyr315Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,052 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0084 ( 8 hom., cov: 32)

Exomes 𝑓: 0.013 ( 183 hom. )

Consequence

P2RX4
NM_002560.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.12

Variant links:

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]

P2RX4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021478474).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0132 (19334/1461798) while in subpopulation NFE AF= 0.0161 (17870/1111928). AF 95% confidence interval is 0.0159. There are 183 homozygotes in gnomad4_exome. There are 9231 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX4	NM_002560.3 link	c.944A>G	p.Tyr315Cys	missense_variant	Exon 9 of 12	ENST00000337233.9	NP_002551.2	Q99571-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX4	ENST00000337233.9 link	c.944A>G	p.Tyr315Cys	missense_variant	Exon 9 of 12	1	NM_002560.3	ENSP00000336607.4		Q99571-1

Frequencies

GnomAD3 genomes

AF:

0.00844

AC:

1284

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00868

AC:

2181

AN:

251412

Hom.:

AF XY:

0.00838

AC XY:

1139

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00937

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00379

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0161

GnomAD4 exome

AF:

0.0132

AC:

19334

AN:

1461798

Hom.:

183

Cov.:

AF XY:

0.0127

AC XY:

9231

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00254

Gnomad4 AMR exome

AF:

0.00937

Gnomad4 ASJ exome

AF:

0.00245

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.00490

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.00977

GnomAD4 genome

AF:

0.00843

AC:

1284

AN:

152254

Hom.:

Cov.:

AF XY:

0.00768

AC XY:

572

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.00889

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0127

Hom.:

Bravo

AF:

0.00919

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0189

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0155

AC:

133

ExAC

AF:

0.00908

AC:

1102

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.021

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.3

M;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.8

D;.;D;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.93

MVP

0.71

MPC

1.2

ClinPred

0.063

GERP RS

3.8

Varity_R

0.83

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over