3-151337857-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022788.5(P2RY12):c.989A>G(p.Glu330Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,614,130 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E330K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (117 hom.)
• Consequence: P2RY12 NM_022788.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.625

Genes affected

P2RY12 (HGNC:18124): (purinergic receptor P2Y12) 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 involved in platelet aggregation, and is a potential target for the treatment of thromboembolisms and other clotting disorders. Mutations in this gene are implicated in bleeding disorder, platelet type 8 (BDPLT8). Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

MED12L (HGNC:16050): (mediator complex subunit 12L) The protein encoded by this gene is part of the Mediator complex, which is involved in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. The Mediator complex links gene-specific transcriptional activators with the basal transcription machinery. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001743257).
• BP6: Variant 3-151337857-T-C is Benign according to our data. Variant chr3-151337857-T-C is described in ClinVar as [Benign]. Clinvar id is 775916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RY12	NM_022788.5	c.989A>G	p.Glu330Gly	missense_variant	3/3	ENST00000302632.4
MED12L	NM_001393769.1	c.2251-12202T>C		intron_variant		ENST00000687756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RY12	ENST00000302632.4	c.989A>G	p.Glu330Gly	missense_variant	3/3	1	NM_022788.5	P1
MED12L	ENST00000687756.1	c.2251-12202T>C		intron_variant			NM_001393769.1	A2

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3313 AN: 152222 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00581 AC: 1459 AN: 251058 Hom.: 55 AF XY: 0.00435 AC XY: 591 AN XY: 135730

Gnomad AFR exome AF: 0.0816

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00225 AC: 3296 AN: 1461790 Hom.: 117 Cov.: 31 AF XY: 0.00191 AC XY: 1387 AN XY: 727186

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00472

GnomAD4 genome AF: 0.0218 AC: 3327 AN: 152340 Hom.: 113 Cov.: 32 AF XY: 0.0208 AC XY: 1551 AN XY: 74500

Gnomad4 AFR AF: 0.0773

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00426 Hom.: 36

Bravo AF: 0.0253

ESP6500AA AF: 0.0704 AC: 310

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00713 AC: 866

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

P2RY12-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.6
Dann	Benign	0.73
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.024
Sift	Benign	0.44	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.027
MVP		0.27
MPC		0.33
ClinPred		0.0024	T
GERP RS		-0.35
Varity_R		0.037
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: rs16846673; hg19: chr3-151055645; COSMIC: COSV56378356; COSMIC: COSV56378356;