NM_001393769.1:c.3448+24C>A

Variant names:

• chr3-151367790-C-A
• rs3732764
• NM_001393769.1:c.3448+24C>A

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.3448+24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,583,232 control chromosomes in the GnomAD database, including 386,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43645 hom., cov: 32)
  • Exomes 𝑓: 0.69 (343113 hom.)
• Consequence: MED12L NM_001393769.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.82
• Publications: 12 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=-0.99).
• BP6: Variant 3-151367790-C-A is Benign according to our data. Variant chr3-151367790-C-A is described in ClinVar as [Benign]. Clinvar id is 1321165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.3448+24C>A		intron_variant	Intron 24 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-180+16902G>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.3448+24C>A		intron_variant	Intron 24 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-180+16902G>T		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.751 AC: 114163 AN: 152004 Hom.: 43594 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.736 AC: 173019 AN: 235172 AF XY: 0.733

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.808

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.841

Gnomad FIN exome AF: 0.683

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.689 AC: 986152 AN: 1431112 Hom.: 343113 Cov.: 36 AF XY: 0.694 AC XY: 491323 AN XY: 708460

African (AFR) AF: 0.897 AC: 29068 AN: 32402

American (AMR) AF: 0.803 AC: 32998 AN: 41086

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 17410 AN: 24868

East Asian (EAS) AF: 0.837 AC: 32753 AN: 39126

South Asian (SAS) AF: 0.831 AC: 68620 AN: 82596

European-Finnish (FIN) AF: 0.677 AC: 35770 AN: 52828

Middle Eastern (MID) AF: 0.834 AC: 4688 AN: 5624

European-Non Finnish (NFE) AF: 0.661 AC: 722661 AN: 1093538

Other (OTH) AF: 0.714 AC: 42184 AN: 59044

GnomAD4 genome AF: 0.751 AC: 114275 AN: 152120 Hom.: 43645 Cov.: 32 AF XY: 0.756 AC XY: 56214 AN XY: 74356

African (AFR) AF: 0.888 AC: 36883 AN: 41526

American (AMR) AF: 0.761 AC: 11621 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2401 AN: 3470

East Asian (EAS) AF: 0.849 AC: 4388 AN: 5170

South Asian (SAS) AF: 0.842 AC: 4053 AN: 4816

European-Finnish (FIN) AF: 0.684 AC: 7233 AN: 10580

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45242 AN: 67976

Other (OTH) AF: 0.761 AC: 1607 AN: 2112

Alfa AF: 0.686 Hom.: 5753

Bravo AF: 0.762

Asia WGS AF: 0.814 AC: 2833 AN: 3478

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	-0.99
CADD	Benign	0.021
DANN	Benign	0.57
PhyloP100		-2.8
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: rs3732764; hg19: chr3-151085578;