rs369083173

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_005120.3(MED12):c.653C>T(p.Thr218Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000744 in 1,209,564 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.000042 ( 0 hom. 7 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 3.98

Variant links:

Genes affected

MED12 (HGNC:11957): (mediator complex subunit 12) The initiation of transcription is controlled in part by a large protein assembly known as the preinitiation complex. A component of this preinitiation complex is a 1.2 MDa protein aggregate called Mediator. This Mediator component binds with a CDK8 subcomplex which contains the protein encoded by this gene, mediator complex subunit 12 (MED12), along with MED13, CDK8 kinase, and cyclin C. The CDK8 subcomplex modulates Mediator-polymerase II interactions and thereby regulates transcription initiation and reinitation rates. The MED12 protein is essential for activating CDK8 kinase. Defects in this gene cause X-linked Opitz-Kaveggia syndrome, also known as FG syndrome, and Lujan-Fryns syndrome. [provided by RefSeq, Aug 2009]

MED12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant where missense usually causes diseases, MED12

BP4

Computational evidence support a benign effect (MetaRNN=0.018629164).

BP6

Variant X-71121070-C-T is Benign according to our data. Variant chrX-71121070-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000395 (44/111421) while in subpopulation AFR AF= 0.0014 (43/30661). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3 linkuse as main transcript	c.653C>T	p.Thr218Met	missense_variant	5/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8 linkuse as main transcript	c.653C>T	p.Thr218Met	missense_variant	5/45	1	NM_005120.3	P4	Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.000404

AC:

AN:

111367

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

33555

show subpopulations

Gnomad AFR

AF:

0.00144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000668

GnomAD3 exomes

AF:

0.000132

AC:

AN:

181730

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

67562

show subpopulations

Gnomad AFR exome

AF:

0.00177

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000419

AC:

AN:

1098143

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363499

show subpopulations

Gnomad4 AFR exome

AF:

0.00144

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.000395

AC:

AN:

111421

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

AN XY:

33619

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000659

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000434

ESP6500AA

AF:

0.00116

AC:

ESP6500EA

AF:

0.000154

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2015	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 06, 2020

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. -

FG syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2021

- -

MED12-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.050

T;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.019

T;T;T

MetaSVM

Benign

-0.83

MutationTaster

Benign

0.63

N;N;N

PrimateAI

Uncertain

0.53

REVEL

Benign

0.059

Sift4G

Benign

0.12

T;T;T

Polyphen

0.47

P;D;D

Vest4

0.26

MVP

0.40

MPC

1.4

ClinPred

0.058

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

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

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