3-151355245-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.2517+6T>C		splice_region_variant, intron_variant	Intron 18 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-179-14485A>G		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.2517+6T>C		splice_region_variant, intron_variant	Intron 18 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-179-14485A>G		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

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

GnomAD3 exomes AF: 0.748 AC: 185309 AN: 247806 Hom.: 70382 AF XY: 0.745 AC XY: 99865 AN XY: 133976

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 SAS exome AF: 0.850

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

Gnomad4 AFR exome AF: 0.930

Gnomad4 AMR exome AF: 0.813

Gnomad4 ASJ exome AF: 0.706

Gnomad4 EAS exome AF: 0.843

Gnomad4 SAS exome AF: 0.846

Gnomad4 FIN exome AF: 0.727

Gnomad4 NFE exome AF: 0.661

Gnomad4 OTH exome AF: 0.722

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

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.771

Gnomad4 ASJ AF: 0.697

Gnomad4 EAS AF: 0.855

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.740

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.771

Alfa AF: 0.704 Hom.: 30013

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs7615865; hg19: chr3-151073033; COSMIC: COSV56381353; COSMIC: COSV56381353;