rs3732755

Variant names:

• chr3-151193618-T-C
• rs3732755
• NM_001393769.1:c.2202T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001393769.1(MED12L):​c.2202T>C​(p.Tyr734Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,613,938 control chromosomes in the GnomAD database, including 3,509 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.086 (1288 hom., cov: 32)
  • Exomes 𝑓: 0.028 (2221 hom.)
• Consequence: MED12L NM_001393769.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.183
• Publications: 11 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]

MED12L Gene-Disease associations (from GenCC):

• Nizon-Isidor syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP7: Synonymous conserved (PhyloP=-0.183 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12L	NM_001393769.1	c.2202T>C	p.Tyr734Tyr	synonymous_variant	Exon 16 of 45	ENST00000687756.1	NP_001380698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12L	ENST00000687756.1	c.2202T>C	p.Tyr734Tyr	synonymous_variant	Exon 16 of 45		NM_001393769.1	ENSP00000508695.1

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13027 AN: 152156 Hom.: 1280 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0712

GnomAD2 exomes AF: 0.0561 AC: 14089 AN: 251314 AF XY: 0.0523

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.214

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0375

GnomAD4 exome AF: 0.0284 AC: 41508 AN: 1461664 Hom.: 2221 Cov.: 31 AF XY: 0.0294 AC XY: 21348 AN XY: 727148

African (AFR) AF: 0.233 AC: 7792 AN: 33458

American (AMR) AF: 0.0430 AC: 1925 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 725 AN: 26132

East Asian (EAS) AF: 0.180 AC: 7155 AN: 39672

South Asian (SAS) AF: 0.0836 AC: 7214 AN: 86244

European-Finnish (FIN) AF: 0.00661 AC: 353 AN: 53398

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5764

European-Non Finnish (NFE) AF: 0.0122 AC: 13600 AN: 1111886

Other (OTH) AF: 0.0436 AC: 2632 AN: 60388

GnomAD4 genome AF: 0.0857 AC: 13048 AN: 152274 Hom.: 1288 Cov.: 32 AF XY: 0.0862 AC XY: 6419 AN XY: 74464

African (AFR) AF: 0.228 AC: 9475 AN: 41526

American (AMR) AF: 0.0564 AC: 864 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1075 AN: 5178

South Asian (SAS) AF: 0.0953 AC: 460 AN: 4826

European-Finnish (FIN) AF: 0.00640 AC: 68 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 863 AN: 68026

Other (OTH) AF: 0.0705 AC: 149 AN: 2114

Alfa AF: 0.0369 Hom.: 650

Bravo AF: 0.0955

Asia WGS AF: 0.118 AC: 411 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0143

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.78
DANN	Benign	0.69
PhyloP100		-0.18
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3732755; hg19: chr3-150911405; COSMIC: COSV56372745; COSMIC: COSV56372745;