rs3745601

Positions:

• chr19-10113872-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002566.5(P2RY11):​c.259G>A​(p.Ala87Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,609,842 control chromosomes in the GnomAD database, including 15,102 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1578 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13524 hom.)
• Consequence: P2RY11 NM_002566.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19

Genes affected

P2RY11 (HGNC:8540): (purinergic receptor P2Y11) The product of this gene belongs to the family of G-protein coupled receptors. This family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. This receptor is coupled to the stimulation of the phosphoinositide and adenylyl cyclase pathways and behaves as a selective purinoceptor. Naturally occuring read-through transcripts, resulting from intergenic splicing between this gene and an immediately upstream gene (PPAN, encoding peter pan homolog), have been found. The PPAN-P2RY11 read-through mRNA is ubiquitously expressed and encodes a fusion protein that shares identity with each individual gene product. [provided by RefSeq, Jul 2008]

PPAN-P2RY11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012397438).
• BP6: Variant 19-10113872-G-A is Benign according to our data. Variant chr19-10113872-G-A is described in ClinVar as [Benign]. Clinvar id is 3059970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RY11	NM_002566.5	c.259G>A	p.Ala87Thr	missense_variant	2/2	ENST00000321826.5
PPAN-P2RY11	NM_001198690.2	c.*18G>A		3_prime_UTR_variant	13/13
PPAN-P2RY11	NM_001040664.3	c.1519G>A	p.Ala507Thr	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RY11	ENST00000321826.5	c.259G>A	p.Ala87Thr	missense_variant	2/2	1	NM_002566.5	P1
P2RY11	ENST00000471843.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19950 AN: 152076 Hom.: 1573 Cov.: 34

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.162 AC: 39430 AN: 243908 Hom.: 3988 AF XY: 0.160 AC XY: 21243 AN XY: 132526

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.396

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.127 AC: 185843 AN: 1457646 Hom.: 13524 Cov.: 37 AF XY: 0.129 AC XY: 93903 AN XY: 725138

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.315

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.131 AC: 19974 AN: 152196 Hom.: 1578 Cov.: 34 AF XY: 0.137 AC XY: 10179 AN XY: 74422

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.126

Alfa AF: 0.126 Hom.: 2417

Bravo AF: 0.132

TwinsUK AF: 0.109 AC: 404

ALSPAC AF: 0.106 AC: 408

ESP6500AA AF: 0.109 AC: 479

ESP6500EA AF: 0.114 AC: 978

ExAC AF: 0.157 AC: 19036

Asia WGS AF: 0.258 AC: 894 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

P2RY11-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.025
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.083
Sift	Uncertain	0.0050	D;T
Sift4G	Benign	0.14	T;T
Polyphen		0.99	.;D
Vest4		0.14
MPC		0.35
ClinPred		0.023	T
GERP RS		3.5
Varity_R		0.10
gMVP		0.24

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: rs3745601; hg19: chr19-10224548; COSMIC: COSV53450975; COSMIC: COSV53450975;