rs387907360
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong
The NM_005120.3(MED12):c.3443G>A(p.Arg1148His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1148L) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 22)
Consequence
MED12
NM_005120.3 missense
NM_005120.3 missense
Scores
4
3
7
Clinical Significance
Conservation
PhyloP100: 5.54
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 where missense usually causes diseases, MED12
PP5
?
Variant X-71128686-G-A is Pathogenic according to our data. Variant chrX-71128686-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 50279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71128686-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED12 | NM_005120.3 | c.3443G>A | p.Arg1148His | missense_variant | 24/45 | ENST00000374080.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED12 | ENST00000374080.8 | c.3443G>A | p.Arg1148His | missense_variant | 24/45 | 1 | NM_005120.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
FG syndrome 1 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | Reported in males with X-linked Ohdo syndrome and females with nonspecific intellectual disability - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MED12 related disorder (ClinVar ID: VCV000050279). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23395478, 24715367, 30006928). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 23395478). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Blepharophimosis - intellectual disability syndrome, MKB type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 07, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;T
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Benign
Sift4G
Benign
T;T;T
Polyphen
D;P;D
Vest4
MutPred
0.43
.;Gain of catalytic residue at R1148 (P = 0.0794);Gain of catalytic residue at R1148 (P = 0.0794);
MVP
MPC
2.0
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