dbSNP rs10935838: MED12L:c.2251-9600A>G (chr3-151340459-A-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.2251-9600A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 152,590 control chromosomes in the GnomAD database, including 54,971 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 0.85 ( 54834 hom., cov: 33)

Exomes 𝑓: 0.83 ( 137 hom. )

Consequence

MED12L
NM_001393769.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0250

Publications

14 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1 link	c.2251-9600A>G		intron_variant	Intron 16 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5 link	c.-15+137T>C		intron_variant	Intron 2 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.2251-9600A>G		intron_variant	Intron 16 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4 link	c.-15+137T>C		intron_variant	Intron 2 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes

AF:

0.849

AC:

129060

AN:

152076

Hom.:

54804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.756

Gnomad AMR

AF:

0.867

Gnomad ASJ

AF:

0.879

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.900

Gnomad FIN

AF:

0.842

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.832

Gnomad OTH

AF:

0.880

GnomAD4 exome

AF:

0.833

AC:

330

AN:

396

Hom.:

137

AF XY:

0.825

AC XY:

203

AN XY:

246

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.833

AC:

325

AN:

390

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.849

AC:

129144

AN:

152194

Hom.:

54834

Cov.:

AF XY:

0.851

AC XY:

63321

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.862

AC:

35767

AN:

41508

American (AMR)

AF:

0.867

AC:

13260

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

3049

AN:

3470

East Asian (EAS)

AF:

0.849

AC:

4404

AN:

5190

South Asian (SAS)

AF:

0.900

AC:

4346

AN:

4830

European-Finnish (FIN)

AF:

0.842

AC:

8920

AN:

10596

Middle Eastern (MID)

AF:

0.952

AC:

280

AN:

294

European-Non Finnish (NFE)

AF:

0.832

AC:

56584

AN:

67994

Other (OTH)

AF:

0.874

AC:

1846

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1023

2046

3068

4091

5114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.846

Hom.:

38385

Bravo

AF:

0.850

Asia WGS

AF:

0.837

AC:

2905

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.42

(source)

DANN

Benign

0.57

PhyloP100

-0.025

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