rs765417606

Positions:

chrX-71124263-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_005120.3(MED12):c.1849A>G(p.Thr617Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000034 in 1,207,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000029 ( 0 hom. 10 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 8.95

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:

MED12 (HGNC:):

MED12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3 linkuse as main transcript	c.1849A>G	p.Thr617Ala	missense_variant	13/45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 linkuse as main transcript	c.1849A>G	p.Thr617Ala	missense_variant	13/45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0000815

AC:

AN:

110489

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

32831

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000479

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:

0.0000759

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

181757

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

67587

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000613

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1096741

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362107

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000285

Gnomad4 OTH exome

AF:

0.0000652

GnomAD4 genome

AF:

0.0000815

AC:

AN:

110489

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

32831

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000479

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000759

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000178

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326637) -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 29, 2016	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Apr 23, 2013

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2018

The p.T617A variant (also known as c.1849A>G), located in coding exon 13 of the MED12 gene, results from an A to G substitution at nucleotide position 1849. The threonine at codon 617 is replaced by alanine, an amino acid with similar properties. This alteration was identified in an individual with autism, craniofacial dysmorphic features, and it was inherited from his mother (Lee H et al. JAMA, 2014 Nov;312:1880-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. -

FG syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.0089

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

T;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;D;T

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.8

.;M;M

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.9

.;D;D

REVEL

Uncertain

0.55

Sift

Benign

0.053

.;T;T

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.55

MutPred

0.35

.;Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);

MVP

0.88

MPC

2.0

ClinPred

0.78

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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