NM_001393769.1:c.2251-10205G>A

Variant names:

• chr3-151339854-G-A
• rs2046934
• NM_001393769.1:c.2251-10205G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001393769.1(MED12L):​c.2251-10205G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 152,118 control chromosomes in the GnomAD database, including 54,767 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 (54767 hom., cov: 32)
• Consequence: MED12L NM_001393769.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• Publications: 77 publications found

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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• 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	c.2251-10205G>A		intron_variant	Intron 16 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-15+742C>T		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	c.2251-10205G>A		intron_variant	Intron 16 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-15+742C>T		intron_variant	Intron 2 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.848 AC: 128950 AN: 152000 Hom.: 54738 Cov.: 32

Gnomad AFR AF: 0.860

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

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

GnomAD4 genome AF: 0.848 AC: 129033 AN: 152118 Hom.: 54767 Cov.: 32 AF XY: 0.851 AC XY: 63241 AN XY: 74350

African (AFR) AF: 0.860 AC: 35713 AN: 41512

American (AMR) AF: 0.867 AC: 13232 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.879 AC: 3050 AN: 3470

East Asian (EAS) AF: 0.848 AC: 4405 AN: 5192

South Asian (SAS) AF: 0.900 AC: 4340 AN: 4824

European-Finnish (FIN) AF: 0.842 AC: 8911 AN: 10578

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56568 AN: 67964

Other (OTH) AF: 0.874 AC: 1846 AN: 2112

Alfa AF: 0.837 Hom.: 103312

Bravo AF: 0.850

Asia WGS AF: 0.835 AC: 2897 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.50
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2046934; hg19: chr3-151057642;