3-151338011-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022788.5(P2RY12):c.835G>A(p.Val279Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V279A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: P2RY12 NM_022788.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0750

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15372658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P2RY12	NM_022788.5	c.835G>A	p.Val279Met	missense_variant	3/3	ENST00000302632.4
MED12L	NM_001393769.1	c.2251-12048C>T		intron_variant		ENST00000687756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P2RY12	ENST00000302632.4	c.835G>A	p.Val279Met	missense_variant	3/3	1	NM_022788.5	P1
MED12L	ENST00000687756.1	c.2251-12048C>T		intron_variant			NM_001393769.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This missense change has been observed in individual(s) with P2RY12-related conditions (PMID: 28983057). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 279 of the P2RY12 protein (p.Val279Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.045
Sift	Benign	0.19	T
Sift4G	Benign	0.13	T
Polyphen		0.12	B
Vest4		0.16
MutPred		0.72		Loss of ubiquitination at K280 (P = 0.0777);
MVP		0.21
MPC		0.53
ClinPred		0.30	T
GERP RS		0.24
Varity_R		0.089
gMVP		0.30

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: rs1751253057; hg19: chr3-151055799;