Genetic Variant MED12L:c.2251-7779C>T (chr3-151342280-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001393769.1(MED12L):c.2251-7779C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,136 control chromosomes in the GnomAD database, including 7,553 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7553 hom., cov: 32)

Consequence

MED12L
NM_001393769.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00300

Publications

21 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1 link	c.2251-7779C>T		intron_variant	Intron 16 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5 link	c.-179-1520G>A		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.2251-7779C>T		intron_variant	Intron 16 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4 link	c.-179-1520G>A		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes

AF:

0.309

AC:

46998

AN:

152020

Hom.:

7546

Cov.:

show subpopulations

Gnomad AFR

AF:

0.274

Gnomad AMI

AF:

0.379

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.449

Gnomad EAS

AF:

0.492

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.279

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.287

Gnomad OTH

AF:

0.352

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.309

AC:

47035

AN:

152136

Hom.:

7553

Cov.:

AF XY:

0.315

AC XY:

23405

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.274

AC:

11372

AN:

41482

American (AMR)

AF:

0.373

AC:

5691

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

1555

AN:

3466

East Asian (EAS)

AF:

0.492

AC:

2549

AN:

5178

South Asian (SAS)

AF:

0.444

AC:

2145

AN:

4826

European-Finnish (FIN)

AF:

0.279

AC:

2955

AN:

10604

Middle Eastern (MID)

AF:

0.449

AC:

131

AN:

292

European-Non Finnish (NFE)

AF:

0.287

AC:

19546

AN:

67996

Other (OTH)

AF:

0.353

AC:

746

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1720

3440

5159

6879

8599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.279

Hom.:

3313

Bravo

AF:

0.315

Asia WGS

AF:

0.423

AC:

1474

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.3

(source)

DANN

Benign

0.15

PhyloP100

0.0030

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over