3-151156270-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_001393769.1(MED12L):c.666G>T(p.Glu222Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

MED12L
NM_001393769.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.275

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant where missense usually causes diseases, MED12L

BP4

Computational evidence support a benign effect (MetaRNN=0.0199759).

BP6

Variant 3-151156270-G-T is Benign according to our data. Variant chr3-151156270-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2357131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-151156270-G-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12L	NM_001393769.1 linkuse as main transcript	c.666G>T	p.Glu222Asp	missense_variant	6/45	ENST00000687756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12L	ENST00000687756.1 linkuse as main transcript	c.666G>T	p.Glu222Asp	missense_variant	6/45		NM_001393769.1	A2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000288

AC:

AN:

249788

Hom.:

AF XY:

0.000348

AC XY:

AN XY:

134978

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000363

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000494

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000222

AC:

325

AN:

1460816

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

190

AN XY:

726654

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000372

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000231

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000217

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000379

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.64

Cadd

Benign

1.0

Dann

Benign

0.48

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.66

N;N;N;.

MutationTaster

Benign

0.72

D;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.84

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.86

T;T;T;T

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.075

MutPred

0.20

Loss of glycosylation at P221 (P = 0.0507);Loss of glycosylation at P221 (P = 0.0507);Loss of glycosylation at P221 (P = 0.0507);Loss of glycosylation at P221 (P = 0.0507);

MVP

0.043

MPC

0.36

ClinPred

0.0038

GERP RS

-4.3

Varity_R

0.050

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over