rs3732765

Positions:

• chr3-151372636-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001393769.1(MED12L):​c.3734G>A​(p.Arg1245Gln) variant causes a missense change. The variant allele was found at a frequency of 0.339 in 1,613,148 control chromosomes in the GnomAD database, including 98,006 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7195 hom., cov: 33)
  • Exomes 𝑓: 0.35 (90811 hom.)
• Consequence: MED12L NM_001393769.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.96

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED12L. . Gene score misZ 3.132 (greater than the threshold 3.09). Trascript score misZ 3.991 (greater than threshold 3.09). GenCC has associacion of gene with Nizon-Isidor syndrome, autosomal dominant non-syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025772154).
• BP6: Variant 3-151372636-G-A is Benign according to our data. Variant chr3-151372636-G-A is described in ClinVar as [Benign]. Clinvar id is 1321166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.3734G>A	p.Arg1245Gln	missense_variant	27/45	ENST00000687756.1	NP_001380698.1
P2RY12	NM_022788.5	c.-180+12056C>T		intron_variant		ENST00000302632.4	NP_073625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1	c.3734G>A	p.Arg1245Gln	missense_variant	27/45		NM_001393769.1	ENSP00000508695.1
P2RY12	ENST00000302632.4	c.-180+12056C>T		intron_variant		1	NM_022788.5	ENSP00000307259.4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42246 AN: 151992 Hom.: 7200 Cov.: 33

Gnomad AFR AF: 0.0872

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.309 AC: 77623 AN: 251044 Hom.: 13192 AF XY: 0.316 AC XY: 42838 AN XY: 135658

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.264

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.345 AC: 504606 AN: 1461038 Hom.: 90811 Cov.: 35 AF XY: 0.345 AC XY: 250927 AN XY: 726858

Gnomad4 AFR exome AF: 0.0689

Gnomad4 AMR exome AF: 0.284

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.398

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.323

GnomAD4 genome AF: 0.278 AC: 42243 AN: 152110 Hom.: 7195 Cov.: 33 AF XY: 0.278 AC XY: 20664 AN XY: 74330

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.313

Alfa AF: 0.352 Hom.: 23905

Bravo AF: 0.262

TwinsUK AF: 0.369 AC: 1368

ALSPAC AF: 0.353 AC: 1362

ESP6500AA AF: 0.0819 AC: 361

ESP6500EA AF: 0.376 AC: 3235

ExAC AF: 0.306 AC: 37134

Asia WGS AF: 0.171 AC: 595 AN: 3478

EpiCase AF: 0.376

EpiControl AF: 0.370

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nizon-Isidor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	0.062
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.12
Sift	Benign	0.58	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.30	B;P
Vest4		0.18
MPC		0.46
ClinPred		0.025	T
GERP RS		5.0
Varity_R		0.076
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs3732765; hg19: chr3-151090424; COSMIC: COSV56372833;