X-71127931-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP2PP5BP4
The NM_005120.3(MED12):c.3020A>G(p.Asn1007Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. N1007N) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
MED12
NM_005120.3 missense
NM_005120.3 missense
Scores
2
3
9
Clinical Significance
Conservation
PhyloP100: 8.93
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, MED12
PP5
?
Variant X-71127931-A-G is Pathogenic according to our data. Variant chrX-71127931-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11521.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-71127931-A-G is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.27516586).. Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED12 | NM_005120.3 | c.3020A>G | p.Asn1007Ser | missense_variant | 22/45 | ENST00000374080.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED12 | ENST00000374080.8 | c.3020A>G | p.Asn1007Ser | missense_variant | 22/45 | 1 | NM_005120.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
not provided Pathogenic:2
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 | - | - - |
X-linked intellectual disability with marfanoid habitus Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 08, 2008 | - - |
FG syndrome 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | Recurrent variant in persons with Lujan syndrome - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;T
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
REVEL
Benign
Sift4G
Benign
T;T;T
Polyphen
B;B;B
Vest4
MutPred
0.64
.;Loss of catalytic residue at N1007 (P = 0.0205);Loss of catalytic residue at N1007 (P = 0.0205);
MVP
MPC
1.2
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