NM_001393769.1:c.3864+409G>A

Variant names:

• chr3-151373175-G-A
• rs9859538
• NM_001393769.1:c.3864+409G>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.3864+409G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 151,826 control chromosomes in the GnomAD database, including 15,146 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 0.41 (15146 hom., cov: 31)
• Consequence: MED12L NM_001393769.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.542
• Publications: 27 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.3864+409G>A		intron_variant	Intron 27 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-180+11517C>T		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	c.3864+409G>A		intron_variant	Intron 27 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-180+11517C>T		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62182 AN: 151708 Hom.: 15148 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.410 AC: 62180 AN: 151826 Hom.: 15146 Cov.: 31 AF XY: 0.404 AC XY: 29963 AN XY: 74192

African (AFR) AF: 0.165 AC: 6849 AN: 41442

American (AMR) AF: 0.413 AC: 6308 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1811 AN: 3470

East Asian (EAS) AF: 0.136 AC: 699 AN: 5144

South Asian (SAS) AF: 0.331 AC: 1592 AN: 4806

European-Finnish (FIN) AF: 0.541 AC: 5681 AN: 10502

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.554 AC: 37612 AN: 67900

Other (OTH) AF: 0.446 AC: 935 AN: 2096

Alfa AF: 0.491 Hom.: 39347

Bravo AF: 0.390

Asia WGS AF: 0.219 AC: 762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.75
PhyloP100		-0.54
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: rs9859538; hg19: chr3-151090963;