NM_001393769.1:c.2251-1622C>T

Variant names:

• chr3-151348437-C-T
• rs11715892
• NM_001393769.1:c.2251-1622C>T

Variant summary

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

The NM_001393769.1(MED12L):​c.2251-1622C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 151,410 control chromosomes in the GnomAD database, including 3,162 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 0.18 (3162 hom., cov: 30)
• Consequence: MED12L NM_001393769.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.512
• Publications: 3 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.2251-1622C>T		intron_variant	Intron 16 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-179-7677G>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	c.2251-1622C>T		intron_variant	Intron 16 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-179-7677G>A		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27795 AN: 151306 Hom.: 3160 Cov.: 30

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.213

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

GnomAD4 genome AF: 0.184 AC: 27792 AN: 151410 Hom.: 3162 Cov.: 30 AF XY: 0.188 AC XY: 13920 AN XY: 73914

African (AFR) AF: 0.0428 AC: 1766 AN: 41302

American (AMR) AF: 0.210 AC: 3187 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 953 AN: 3464

East Asian (EAS) AF: 0.161 AC: 826 AN: 5142

South Asian (SAS) AF: 0.329 AC: 1580 AN: 4800

European-Finnish (FIN) AF: 0.254 AC: 2615 AN: 10308

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.236 AC: 16052 AN: 67906

Other (OTH) AF: 0.214 AC: 452 AN: 2108

Alfa AF: 0.209 Hom.: 438

Bravo AF: 0.172

Asia WGS AF: 0.229 AC: 796 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.0
DANN	Benign	0.80
PhyloP100		0.51
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: rs11715892; hg19: chr3-151066225;