X-71140687-A-G

Position:

chrX-71140687-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_005120.3(MED12):c.6097A>G(p.Met2033Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,207,745 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000064 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000047 ( 0 hom. 24 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.17

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 -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED12. . Gene score misZ 6.5797 (greater than the threshold 3.09). GenCC has associacion of gene with 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=0.028584987).

BP6

Variant X-71140687-A-G is Benign according to our data. Variant chrX-71140687-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213627.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3 linkuse as main transcript	c.6097A>G	p.Met2033Val	missense_variant	42/45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 linkuse as main transcript	c.6097A>G	p.Met2033Val	missense_variant	42/45	1	NM_005120.3	ENSP00000363193	P4	Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0000640

AC:

AN:

109451

Hom.:

Cov.:

AF XY:

0.0000314

AC XY:

AN XY:

31861

show subpopulations

Gnomad AFR

AF:

0.0000667

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000400

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000761

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000555

AC:

AN:

180034

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

67098

show subpopulations

Gnomad AFR exome

AF:

0.000161

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000221

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000251

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

AN:

1098238

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

363592

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000368

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.0000639

AC:

AN:

109507

Hom.:

Cov.:

AF XY:

0.0000313

AC XY:

AN XY:

31927

show subpopulations

Gnomad4 AFR

AF:

0.0000666

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000401

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000762

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type;C5399762:FG syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

Has not been previously published as pathogenic or benign to our knowledge -

FG syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

MED12-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2023

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

0.060

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.057

T;.;T

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.80

.;N;N

REVEL

Benign

0.024

Sift

Uncertain

0.027

.;D;D

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.39

MVP

0.27

MPC

0.72

ClinPred

0.0082

GERP RS

0.56

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.091

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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