Genetic Variant MED12L:c.4591-323C>T (chr3-151382333-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.4591-323C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 151,934 control chromosomes in the GnomAD database, including 5,897 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 0.27 ( 5897 hom., cov: 32)

Consequence

MED12L
NM_001393769.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.576

Publications

3 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 (SAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1 link	c.4591-323C>T		intron_variant	Intron 32 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5 link	c.-180+2359G>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.4591-323C>T		intron_variant	Intron 32 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4 link	c.-180+2359G>A		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes

AF:

0.267

AC:

40534

AN:

151816

Hom.:

5890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.381

Gnomad FIN

AF:

0.219

Gnomad MID

AF:

0.217

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.233

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

GnomAD4 genome

AF:

0.267

AC:

40574

AN:

151934

Hom.:

5897

Cov.:

AF XY:

0.271

AC XY:

20143

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.380

AC:

15740

AN:

41432

American (AMR)

AF:

0.255

AC:

3898

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

490

AN:

3468

East Asian (EAS)

AF:

0.291

AC:

1502

AN:

5170

South Asian (SAS)

AF:

0.381

AC:

1834

AN:

4814

European-Finnish (FIN)

AF:

0.219

AC:

2309

AN:

10548

Middle Eastern (MID)

AF:

0.205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.208

AC:

14160

AN:

67934

Other (OTH)

AF:

0.231

AC:

487

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1457

2914

4371

5828

7285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.164

Hom.:

462

Bravo

AF:

0.272

Asia WGS

AF:

0.322

AC:

1121

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.1

(source)

DANN

Benign

0.44

PhyloP100

-0.58

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over