rs10935841

Variant names:

• chr3-151383903-C-T
• rs10935841
• NM_001393769.1:c.4790+15C>T

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.4790+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,597,770 control chromosomes in the GnomAD database, including 101,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9392 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92453 hom.)
• Consequence: MED12L NM_001393769.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.27
• 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=-0.89).
• BP6: Variant 3-151383903-C-T is Benign according to our data. Variant chr3-151383903-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.4790+15C>T		intron_variant	Intron 34 of 44	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-180+789G>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.4790+15C>T		intron_variant	Intron 34 of 44		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-180+789G>A		intron_variant	Intron 1 of 2	1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52752 AN: 151848 Hom.: 9388 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.363

GnomAD2 exomes AF: 0.329 AC: 80664 AN: 245400 AF XY: 0.331

Gnomad AFR exome AF: 0.326

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.353 AC: 510708 AN: 1445804 Hom.: 92453 Cov.: 26 AF XY: 0.352 AC XY: 253550 AN XY: 719776

African (AFR) AF: 0.321 AC: 10646 AN: 33188

American (AMR) AF: 0.299 AC: 13186 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8200 AN: 25980

East Asian (EAS) AF: 0.141 AC: 5584 AN: 39538

South Asian (SAS) AF: 0.270 AC: 23066 AN: 85422

European-Finnish (FIN) AF: 0.399 AC: 21215 AN: 53234

Middle Eastern (MID) AF: 0.341 AC: 1946 AN: 5712

European-Non Finnish (NFE) AF: 0.370 AC: 406545 AN: 1098760

Other (OTH) AF: 0.340 AC: 20320 AN: 59814

GnomAD4 genome AF: 0.347 AC: 52790 AN: 151966 Hom.: 9392 Cov.: 32 AF XY: 0.346 AC XY: 25666 AN XY: 74274

African (AFR) AF: 0.329 AC: 13629 AN: 41428

American (AMR) AF: 0.318 AC: 4858 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3470

East Asian (EAS) AF: 0.133 AC: 692 AN: 5188

South Asian (SAS) AF: 0.268 AC: 1292 AN: 4816

European-Finnish (FIN) AF: 0.401 AC: 4232 AN: 10548

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25612 AN: 67940

Other (OTH) AF: 0.360 AC: 761 AN: 2112

Alfa AF: 0.359 Hom.: 3027

Bravo AF: 0.341

Asia WGS AF: 0.189 AC: 660 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 07, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nizon-Isidor syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.012
DANN	Benign	0.41
PhyloP100		-1.3
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: rs10935841; hg19: chr3-151101691; COSMIC: COSV56376979;