3-151355245-T-C

Variant names:

• chr3-151355245-T-C
• rs7615865
• NM_001393769.1:c.2517+6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001393769.1(MED12L):​c.2517+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,590,704 control chromosomes in the GnomAD database, including 395,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45424 hom., cov: 31)
  • Exomes 𝑓: 0.69 (350289 hom.)
• Consequence: MED12L NM_001393769.1 splice_region, intron
• Scores: Splicing: ADA: 0.002986
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.661
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-151355245-T-C is Benign according to our data. Variant chr3-151355245-T-C is described in ClinVar as Benign. ClinVar VariationId is 1321163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.912 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	NM_001393769.1	MANE Select	c.2517+6T>C		splice_region intron	N/A	NP_001380698.1
	P2RY12	NM_022788.5	MANE Select	c.-179-14485A>G		intron	N/A	NP_073625.1
	MED12L	NM_053002.6		c.2412+6T>C		splice_region intron	N/A	NP_443728.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12L	ENST00000687756.1	MANE Select	c.2517+6T>C		splice_region intron	N/A	ENSP00000508695.1
	P2RY12	ENST00000302632.4	TSL:1 MANE Select	c.-179-14485A>G		intron	N/A	ENSP00000307259.4
	MED12L	ENST00000474524.5	TSL:1	c.2412+6T>C		splice_region intron	N/A	ENSP00000417235.1

Frequencies

GnomAD3 genomes AF: 0.765 AC: 116267 AN: 151978 Hom.: 45371 Cov.: 31

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.773

GnomAD2 exomes AF: 0.748 AC: 185309 AN: 247806 AF XY: 0.745

Gnomad AFR exome AF: 0.926

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.849

Gnomad FIN exome AF: 0.735

Gnomad NFE exome AF: 0.665

Gnomad OTH exome AF: 0.728

GnomAD4 exome AF: 0.694 AC: 998275 AN: 1438608 Hom.: 350289 Cov.: 25 AF XY: 0.698 AC XY: 500692 AN XY: 716958

African (AFR) AF: 0.930 AC: 30568 AN: 32874

American (AMR) AF: 0.813 AC: 35410 AN: 43544

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 18294 AN: 25920

East Asian (EAS) AF: 0.843 AC: 33345 AN: 39544

South Asian (SAS) AF: 0.846 AC: 71991 AN: 85062

European-Finnish (FIN) AF: 0.727 AC: 38786 AN: 53362

Middle Eastern (MID) AF: 0.847 AC: 4848 AN: 5726

European-Non Finnish (NFE) AF: 0.661 AC: 722010 AN: 1093010

Other (OTH) AF: 0.722 AC: 43023 AN: 59566

GnomAD4 genome AF: 0.765 AC: 116382 AN: 152096 Hom.: 45424 Cov.: 31 AF XY: 0.772 AC XY: 57423 AN XY: 74342

African (AFR) AF: 0.919 AC: 38167 AN: 41518

American (AMR) AF: 0.771 AC: 11768 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 2419 AN: 3470

East Asian (EAS) AF: 0.855 AC: 4420 AN: 5172

South Asian (SAS) AF: 0.857 AC: 4133 AN: 4824

European-Finnish (FIN) AF: 0.740 AC: 7814 AN: 10566

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45173 AN: 67954

Other (OTH) AF: 0.771 AC: 1629 AN: 2114

Alfa AF: 0.703 Hom.: 81914

Bravo AF: 0.773

Asia WGS AF: 0.824 AC: 2867 AN: 3478

EpiCase AF: 0.675

EpiControl AF: 0.676

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nizon-Isidor syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		-0.66
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.17
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: rs7615865; hg19: chr3-151073033; COSMIC: COSV56381353; COSMIC: COSV56381353;