3-151372636-G-A

Variant names:

• chr3-151372636-G-A
• rs3732765
• NM_001393769.1:c.3734G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001393769.1(MED12L):​c.3734G>A​(p.Arg1245Gln) variant causes a missense change. The variant allele was found at a frequency of 0.339 in 1,613,148 control chromosomes in the GnomAD database, including 98,006 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7195 hom., cov: 33)
  • Exomes 𝑓: 0.35 (90811 hom.)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.96
• Publications: 47 publications found

Genes affected

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]

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]

P2RY12 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 8

  Inheritance: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025772154).
• BP6: Variant 3-151372636-G-A is Benign according to our data. Variant chr3-151372636-G-A is described in ClinVar as Benign. ClinVar VariationId is 1321166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393769.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	NM_001393769.1	MANE Select	c.3734G>A	p.Arg1245Gln	missense	Exon 27 of 45	NP_001380698.1
	P2RY12	NM_022788.5	MANE Select	c.-180+12056C>T		intron	N/A	NP_073625.1
	MED12L	NM_053002.6		c.3629G>A	p.Arg1210Gln	missense	Exon 26 of 44	NP_443728.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	ENST00000687756.1	MANE Select	c.3734G>A	p.Arg1245Gln	missense	Exon 27 of 45	ENSP00000508695.1
	MED12L	ENST00000474524.5	TSL:1	c.3629G>A	p.Arg1210Gln	missense	Exon 25 of 43	ENSP00000417235.1
	P2RY12	ENST00000302632.4	TSL:1 MANE Select	c.-180+12056C>T		intron	N/A	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42246 AN: 151992 Hom.: 7200 Cov.: 33

Gnomad AFR AF: 0.0872

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.313

GnomAD2 exomes AF: 0.309 AC: 77623 AN: 251044 AF XY: 0.316

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.345 AC: 504606 AN: 1461038 Hom.: 90811 Cov.: 35 AF XY: 0.345 AC XY: 250927 AN XY: 726858

African (AFR) AF: 0.0689 AC: 2306 AN: 33466

American (AMR) AF: 0.284 AC: 12721 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8239 AN: 26120

East Asian (EAS) AF: 0.140 AC: 5555 AN: 39660

South Asian (SAS) AF: 0.266 AC: 22927 AN: 86224

European-Finnish (FIN) AF: 0.398 AC: 21259 AN: 53398

Middle Eastern (MID) AF: 0.327 AC: 1882 AN: 5762

European-Non Finnish (NFE) AF: 0.369 AC: 410233 AN: 1111330

Other (OTH) AF: 0.323 AC: 19484 AN: 60360

GnomAD4 genome AF: 0.278 AC: 42243 AN: 152110 Hom.: 7195 Cov.: 33 AF XY: 0.278 AC XY: 20664 AN XY: 74330

African (AFR) AF: 0.0869 AC: 3611 AN: 41544

American (AMR) AF: 0.296 AC: 4525 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1118 AN: 3466

East Asian (EAS) AF: 0.133 AC: 691 AN: 5186

South Asian (SAS) AF: 0.263 AC: 1266 AN: 4820

European-Finnish (FIN) AF: 0.399 AC: 4210 AN: 10546

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25574 AN: 67956

Other (OTH) AF: 0.313 AC: 660 AN: 2112

Alfa AF: 0.337 Hom.: 31512

Bravo AF: 0.262

TwinsUK AF: 0.369 AC: 1368

ALSPAC AF: 0.353 AC: 1362

ESP6500AA AF: 0.0819 AC: 361

ESP6500EA AF: 0.376 AC: 3235

ExAC AF: 0.306 AC: 37134

Asia WGS AF: 0.171 AC: 595 AN: 3478

EpiCase AF: 0.376

EpiControl AF: 0.370

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nizon-Isidor syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.12
Sift	Benign	0.58	T
Sift4G	Benign	0.30	T
Polyphen		0.30	B
Vest4		0.18
MPC		0.46
ClinPred		0.025	T
GERP RS		5.0
Varity_R		0.076
gMVP		0.27
Mutation Taster		=99/1	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: rs3732765; hg19: chr3-151090424; COSMIC: COSV56372833;