Genetic Variant NM_002559.5:c.211G>A (chr11-57346635-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002559.5(P2RX3):c.211G>A(p.Ala71Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,614,098 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.032 ( 94 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1351 hom. )

Consequence

P2RX3
NM_002559.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.64

Publications

19 publications found

Variant links:

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]

P2RX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033548772).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0318 (4836/152296) while in subpopulation NFE AF = 0.0431 (2934/68030). AF 95% confidence interval is 0.0418. There are 94 homozygotes in GnomAd4. There are 2408 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 94 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX3	NM_002559.5 link	c.211G>A	p.Ala71Thr	missense_variant	Exon 2 of 12	ENST00000263314.3	NP_002550.2	P56373

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX3	ENST00000263314.3 link	c.211G>A	p.Ala71Thr	missense_variant	Exon 2 of 12	1	NM_002559.5	ENSP00000263314.2		P56373

Frequencies

GnomAD3 genomes

AF:

0.0318

AC:

4837

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00910

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0269

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0431

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0377

AC:

9472

AN:

251376

AF XY:

0.0385

show subpopulations

Gnomad AFR exome

AF:

0.00941

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.0201

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.0722

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0419

GnomAD4 exome

AF:

0.0400

AC:

58536

AN:

1461802

Hom.:

1351

Cov.:

AF XY:

0.0402

AC XY:

29221

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00980

AC:

328

AN:

33476

American (AMR)

AF:

0.0366

AC:

1638

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

556

AN:

26136

East Asian (EAS)

AF:

0.00244

AC:

AN:

39700

South Asian (SAS)

AF:

0.0441

AC:

3805

AN:

86250

European-Finnish (FIN)

AF:

0.0701

AC:

3745

AN:

53408

Middle Eastern (MID)

AF:

0.0256

AC:

147

AN:

5742

European-Non Finnish (NFE)

AF:

0.0415

AC:

46092

AN:

1111980

Other (OTH)

AF:

0.0352

AC:

2128

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

3076

6152

9229

12305

15381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1716

3432

5148

6864

8580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0318

AC:

4836

AN:

152296

Hom.:

Cov.:

AF XY:

0.0323

AC XY:

2408

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00910

AC:

378

AN:

41546

American (AMR)

AF:

0.0269

AC:

411

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.00154

AC:

AN:

5190

South Asian (SAS)

AF:

0.0365

AC:

176

AN:

4826

European-Finnish (FIN)

AF:

0.0723

AC:

767

AN:

10612

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0431

AC:

2934

AN:

68030

Other (OTH)

AF:

0.0265

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

232

463

695

926

1158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0370

Hom.:

356

Bravo

AF:

0.0280

TwinsUK

AF:

0.0386

AC:

143

ALSPAC

AF:

0.0387

AC:

149

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.0432

AC:

371

ExAC

AF:

0.0374

AC:

4545

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0368

EpiControl

AF:

0.0365

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.20

.;N

PhyloP100

2.6

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.4

.;N

REVEL

Benign

0.092

Sift

Benign

0.14

.;T

Sift4G

Benign

0.48

T;T

Polyphen

0.85

.;P

Vest4

0.035

MPC

0.26

ClinPred

0.026

GERP RS

4.7

Varity_R

0.075

gMVP

0.52

Mutation Taster

=80/20

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over