X-71127367-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong
The NM_005120.3(MED12):c.2881C>T(p.Arg961Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
MED12
NM_005120.3 missense
NM_005120.3 missense
Scores
7
7
3
Clinical Significance
Conservation
PhyloP100: 5.85
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 108 curated benign missense variants. GenCC has associacion of the 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.
PP5
Variant X-71127367-C-T is Pathogenic according to our data. Variant chrX-71127367-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71127367-C-T is described in Lovd as [Pathogenic]. Variant chrX-71127367-C-T is described in Lovd as [Pathogenic]. Variant chrX-71127367-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2022 | Published functional studies demonstrate prevention of normal suppression of GLI3, resulting in enhanced SHH signaling pathway activation (Zhou et al., 2012); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17334363, 31536828, 20981778, 26350204, 28369444, 31623504, 31618753, 33710394, 23091001, 19938245) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 01, 2020 | - - |
FG syndrome 1 Pathogenic:3Other:1
| not provided, no classification provided | literature only | GeneReviews | - | Most common pathogenic variant in persons with FG syndrome type 1 - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 08, 2008 | - - |
| Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 5-year-old male with mitochondrial disease, developmental delay, hypogammaglobulinemia, GI dysmotility, hypotonia, scoliosis, strabismus, dysmorphisms, failure to thrive, dilated cardiomyopathy - |
Blepharophimosis - intellectual disability syndrome, MKB type Pathogenic:2
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 17334363, 19938245, 28369444, 20981778, 26350204, 23091001] - |
Imperforate anus;C0175754:Corpus callosum, agenesis of;C0424503:Abnormal facial shape;C0426891:Broad thumb;C0557874:Global developmental delay;C3714756:Intellectual disability Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 27, 2016 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2020 | The c.2881C>T (p.R961W) alteration is located in coding exon 21 of the MED12 gene. This alteration results from a C to T substitution at nucleotide position 2881, causing the arginine (R) at amino acid position 961 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the MED12 c.2881C>T alteration was not observed, with coverage at this position. The c.2881C>T (p.R961W) alteration has been reported in multiple unrelated males with neurodevelopmental disorders (Risheg, 2007; Graham, 2008; Clark, 2009; Lyons, 2009). The p.R961 amino acid is not conserved in available vertebrate species. Functional analyses demonstrated that the p.R961W alteration in patient-derived cells showed increased signaling and/or activation of downstream genes and this dysregulated signaling contributes to the phenotypes of patients with FG and Lujan syndromes (Zhou, 2012; Donnio, 2017). The in silico prediction for the p.R961W alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
FG syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 14, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 961 of the MED12 protein (p.Arg961Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Opitz-Kaveggia syndrome (PMID: 17334363, 18805826, 19938245). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11520). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MED12 protein function. Experimental studies have shown that this missense change affects MED12 function (PMID: 23091001). For these reasons, this variant has been classified as Pathogenic. - |
X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type;C5399762:FG syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Intellectual disability Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Center for Statistical Genetics, Columbia University | Oct 16, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;D
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;N;N
REVEL
Pathogenic
Sift
Uncertain
.;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
0.67
.;Loss of disorder (P = 0.015);Loss of disorder (P = 0.015);
MVP
MPC
2.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at