rs3745601

Variant names:

• chr19-10113872-G-A
• rs3745601
• NM_002566.5:c.259G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1578 hom., cov: 34)
  • Exomes 𝑓: 0.13 (13524 hom.)
• Consequence: P2RY11 NM_002566.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.19
• Publications: 47 publications found

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:33526): (PPAN-P2RY11 readthrough) This locus represents naturally occurring read-through transcription between the adjacent PPAN and P2RY11 genes. Alternative splicing results in two transcript variants, one of which encodes a fusion protein that shares sequence identity with each individual gene product. This transcript is found to be ubiquitously expressed and is up-regulated by agents inducing granulocytic differentiation. However, its functional significance in vivo remains unclear. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3059970.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
P2RY11	NM_002566.5	c.259G>A	p.Ala87Thr	missense_variant	Exon 2 of 2	ENST00000321826.5	NP_002557.2
PPAN-P2RY11	NM_001040664.3	c.1519G>A	p.Ala507Thr	missense_variant	Exon 13 of 13		NP_001035754.1
PPAN-P2RY11	NM_001198690.2	c.*18G>A		3_prime_UTR_variant	Exon 13 of 13		NP_001185619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RY11	ENST00000321826.5	c.259G>A	p.Ala87Thr	missense_variant	Exon 2 of 2	1	NM_002566.5	ENSP00000323872.4
PPAN-P2RY11	ENST00000393796.4	c.1519G>A	p.Ala507Thr	missense_variant	Exon 13 of 13	1		ENSP00000377385.4
PPAN-P2RY11	ENST00000428358.5	c.*18G>A		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000411918.1
P2RY11	ENST00000471843.1	n.*38G>A		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

GnomAD2 exomes AF: 0.162 AC: 39430 AN: 243908 AF XY: 0.160

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 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

African (AFR) AF: 0.105 AC: 3509 AN: 33466

American (AMR) AF: 0.189 AC: 8430 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3133 AN: 26084

East Asian (EAS) AF: 0.315 AC: 12471 AN: 39642

South Asian (SAS) AF: 0.199 AC: 17131 AN: 86208

European-Finnish (FIN) AF: 0.149 AC: 7545 AN: 50528

Middle Eastern (MID) AF: 0.110 AC: 637 AN: 5766

European-Non Finnish (NFE) AF: 0.112 AC: 124768 AN: 1111060

Other (OTH) AF: 0.136 AC: 8219 AN: 60292

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

African (AFR) AF: 0.106 AC: 4381 AN: 41524

American (AMR) AF: 0.149 AC: 2278 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 404 AN: 3470

East Asian (EAS) AF: 0.361 AC: 1862 AN: 5162

South Asian (SAS) AF: 0.207 AC: 997 AN: 4828

European-Finnish (FIN) AF: 0.149 AC: 1577 AN: 10602

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8044 AN: 68000

Other (OTH) AF: 0.126 AC: 266 AN: 2112

Alfa AF: 0.126 Hom.: 3709

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: no assertion criteria provided

Submissions by phenotype

P2RY11-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
DEOGEN2	Benign	0.043	.;T
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
MutationAssessor	Uncertain	2.1	.;M
PhyloP100		1.2
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
Mutation Taster		=92/8	polymorphism (auto)

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