3-151381953-A-G

Variant names:

• chr3-151381953-A-G
• rs6787801
• NM_001393769.1:c.4591-703A>G

Variant summary

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

The NM_001393769.1(MED12L):​c.4591-703A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,008 control chromosomes in the GnomAD database, including 18,976 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 0.50 (18976 hom., cov: 31)
• Consequence: MED12L NM_001393769.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• Publications: 33 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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393769.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	NM_001393769.1	MANE Select	c.4591-703A>G		intron	N/A	NP_001380698.1	A0A8I5KX78
	P2RY12	NM_022788.5	MANE Select	c.-180+2739T>C		intron	N/A	NP_073625.1	Q9H244
	MED12L	NM_053002.6		c.4486-703A>G		intron	N/A	NP_443728.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	ENST00000687756.1	MANE Select	c.4591-703A>G		intron	N/A	ENSP00000508695.1	A0A8I5KX78
	P2RY12	ENST00000302632.4	TSL:1 MANE Select	c.-180+2739T>C		intron	N/A	ENSP00000307259.4	Q9H244
	MED12L	ENST00000474524.5	TSL:1	c.4486-703A>G		intron	N/A	ENSP00000417235.1	Q86YW9-1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75715 AN: 151888 Hom.: 18965 Cov.: 31

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.528

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

GnomAD4 genome AF: 0.498 AC: 75763 AN: 152008 Hom.: 18976 Cov.: 31 AF XY: 0.500 AC XY: 37167 AN XY: 74286

African (AFR) AF: 0.500 AC: 20716 AN: 41434

American (AMR) AF: 0.442 AC: 6761 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1875 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2108 AN: 5158

South Asian (SAS) AF: 0.483 AC: 2326 AN: 4818

European-Finnish (FIN) AF: 0.555 AC: 5854 AN: 10544

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34241 AN: 67980

Other (OTH) AF: 0.527 AC: 1115 AN: 2114

Alfa AF: 0.493 Hom.: 31597

Bravo AF: 0.490

Asia WGS AF: 0.440 AC: 1532 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.28
DANN	Benign	0.38
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6787801; hg19: chr3-151099741;