rs3732765

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.96

Publications

47 publications found

Variant links:

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]

MED12L links:

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

P2RY12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1 link	c.3734G>A	p.Arg1245Gln	missense_variant	Exon 27 of 45	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5 link	c.-180+12056C>T		intron_variant	Intron 1 of 2	ENST00000302632.4	NP_073625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1 link	c.3734G>A	p.Arg1245Gln	missense_variant	Exon 27 of 45		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4 link	c.-180+12056C>T		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42246

AN:

151992

Hom.:

7200

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.345

AC XY:

250927

AN XY:

726858

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

16371

32742

49112

65483

81854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12640

25280

37920

50560

63200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.278

AC:

42243

AN:

152110

Hom.:

7195

Cov.:

AF XY:

0.278

AC XY:

20664

AN XY:

74330

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.376

AC:

25574

AN:

67956

Other (OTH)

AF:

0.313

AC:

660

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1454

2909

4363

5818

7272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.010

T;.

Eigen

Benign

0.062

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;.

PhyloP100

4.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.12

Sift

Benign

0.58

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.30

B;P

Vest4

0.18

MPC

0.46

ClinPred

0.025

GERP RS

5.0

Varity_R

0.076

gMVP

0.27

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over