NM_005120.3:c.5711C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_005120.3(MED12):c.5711C>T(p.Ala1904Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,209,731 control chromosomes in the GnomAD database, including 5 homozygotes. There are 413 hemizygotes in GnomAD. 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., 26 hem., cov: 22)

Exomes 𝑓: 0.0011 ( 5 hom. 387 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 3.18

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 -19 ACMG points.

PP2

Missense variant in the MED12 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 108 curated benign missense variants. Gene score misZ: 6.5797 (above the threshold of 3.09). GenCC associations: The gene is linked to MED12-related intellectual disability syndrome, X-linked intellectual disability with marfanoid habitus, blepharophimosis - intellectual disability syndrome, MKB type, FG syndrome 1, cholestasis-pigmentary retinopathy-cleft palate syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.003823787).

BP6

Variant X-71137346-C-T is Benign according to our data. Variant chrX-71137346-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71137346-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000896 (100/111661) while in subpopulation AMR AF= 0.00151 (16/10586). AF 95% confidence interval is 0.000948. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.5711C>T	p.Ala1904Val	missense_variant	Exon 39 of 45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.5711C>T	p.Ala1904Val	missense_variant	Exon 39 of 45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.000896

AC:

100

AN:

111610

Hom.:

Cov.:

AF XY:

0.000769

AC XY:

AN XY:

33796

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00717

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00833

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00200

GnomAD3 exomes

AF:

0.00118

AC:

213

AN:

180002

Hom.:

AF XY:

0.00103

AC XY:

AN XY:

66790

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.0000629

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00105

AC:

1156

AN:

1098070

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

387

AN XY:

363426

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

Gnomad4 AMR exome

AF:

0.000597

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.000123

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.000896

AC:

100

AN:

111661

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

AN XY:

33857

show subpopulations

Gnomad4 AFR

AF:

0.000163

Gnomad4 AMR

AF:

0.00151

Gnomad4 ASJ

AF:

0.00717

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000603

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000985

AC:

119

EpiCase

AF:

0.00196

EpiControl

AF:

0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 18, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28152038, 26813965, 24728327) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2Other:1

Nov 09, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

May 18, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MED12-related disorder

Benign:1

Jan 23, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

0.086

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;T

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

.;N;N

REVEL

Benign

0.055

Sift

Benign

0.29

.;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.088

B;B;B

Vest4

0.18

MVP

0.63

MPC

0.79

ClinPred

0.0097

GERP RS

4.8

Varity_R

0.16

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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