Genetic Variant MED12L:c.3327+539C>G (chr3-151366530-C-G) – 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.3327+539C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 152,196 control chromosomes in the GnomAD database, including 45,062 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 0.76 ( 45062 hom., cov: 32)

Consequence

MED12L
NM_001393769.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.115

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=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1 link	c.3327+539C>G		intron_variant	Intron 23 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5 link	c.-180+18162G>C		intron_variant	Intron 1 of 2	ENST00000302632.4	NP_073625.1	Q9H244A8K7T1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1 link	c.3327+539C>G		intron_variant	Intron 23 of 44		NM_001393769.1	ENSP00000508695.1		A0A8I5KX78
P2RY12	ENST00000302632.4 link	c.-180+18162G>C		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4		Q9H244

Frequencies

GnomAD3 genomes

AF:

0.764

AC:

116119

AN:

152078

Hom.:

45008

Cov.:

show subpopulations

Gnomad AFR

AF:

0.891

Gnomad AMI

AF:

0.689

Gnomad AMR

AF:

0.768

Gnomad ASJ

AF:

0.699

Gnomad EAS

AF:

0.855

Gnomad SAS

AF:

0.864

Gnomad FIN

AF:

0.745

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.678

Gnomad OTH

AF:

0.772

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

GnomAD4 genome

AF:

0.764

AC:

116235

AN:

152196

Hom.:

45062

Cov.:

AF XY:

0.771

AC XY:

57363

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.891

AC:

37043

AN:

41552

American (AMR)

AF:

0.769

AC:

11745

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

2425

AN:

3470

East Asian (EAS)

AF:

0.855

AC:

4436

AN:

5186

South Asian (SAS)

AF:

0.863

AC:

4164

AN:

4826

European-Finnish (FIN)

AF:

0.745

AC:

7874

AN:

10576

Middle Eastern (MID)

AF:

0.779

AC:

229

AN:

294

European-Non Finnish (NFE)

AF:

0.678

AC:

46067

AN:

67990

Other (OTH)

AF:

0.769

AC:

1624

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1379

2758

4136

5515

6894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.725

Hom.:

5014

Bravo

AF:

0.770

Asia WGS

AF:

0.825

AC:

2871

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.4

(source)

DANN

Benign

0.55

PhyloP100

-0.12

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