3-151337866-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022788.5(P2RY12):​c.980G>A​(p.Arg327Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

P2RY12
NM_022788.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.180
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05345401).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
P2RY12NM_022788.5 linkc.980G>A p.Arg327Lys missense_variant Exon 3 of 3 ENST00000302632.4 NP_073625.1 Q9H244A8K7T1
MED12LNM_001393769.1 linkc.2251-12193C>T intron_variant Intron 16 of 44 ENST00000687756.1 NP_001380698.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
P2RY12ENST00000302632.4 linkc.980G>A p.Arg327Lys missense_variant Exon 3 of 3 1 NM_022788.5 ENSP00000307259.4 Q9H244
MED12LENST00000687756.1 linkc.2251-12193C>T intron_variant Intron 16 of 44 NM_001393769.1 ENSP00000508695.1 A0A8I5KX78

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1460982
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726814
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152034
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74244
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 13, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.980G>A (p.R327K) alteration is located in exon 3 (coding exon 1) of the P2RY12 gene. This alteration results from a G to A substitution at nucleotide position 980, causing the arginine (R) at amino acid position 327 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
5.2
DANN
Benign
0.71
DEOGEN2
Benign
0.10
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.061
N
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.053
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.99
L
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.30
N
REVEL
Benign
0.077
Sift
Benign
0.56
T
Sift4G
Benign
0.96
T
Polyphen
0.0
B
Vest4
0.075
MutPred
0.31
Gain of ubiquitination at R327 (P = 0.0131);
MVP
0.47
MPC
0.29
ClinPred
0.023
T
GERP RS
0.30
Varity_R
0.044
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1309279839; hg19: chr3-151055654; COSMIC: COSV99853280; COSMIC: COSV99853280; API