rs765417606

Variant summary

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

The NM_005120.3(MED12):ā€‹c.1849A>Gā€‹(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: š‘“ 0.000081 ( 0 hom., 4 hem., cov: 23)
Exomes š‘“: 0.000029 ( 0 hom. 10 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

2
9
6

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]

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
MED12NM_005120.3 linkuse as main transcriptc.1849A>G p.Thr617Ala missense_variant 13/45 ENST00000374080.8 NP_005111.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MED12ENST00000374080.8 linkuse as main transcriptc.1849A>G p.Thr617Ala missense_variant 13/451 NM_005120.3 ENSP00000363193 P4Q93074-1

Frequencies

GnomAD3 genomes
AF:
0.0000815
AC:
9
AN:
110489
Hom.:
0
Cov.:
23
AF XY:
0.000122
AC XY:
4
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:
5
AN:
181757
Hom.:
0
AF XY:
0.0000444
AC XY:
3
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:
32
AN:
1096741
Hom.:
0
Cov.:
31
AF XY:
0.0000276
AC XY:
10
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:
9
AN:
110489
Hom.:
0
Cov.:
23
AF XY:
0.000122
AC XY:
4
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:
3
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 submitterclinical testingGeneDxOct 14, 2021Not 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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 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 submitterclinical testingUCLA Clinical Genomics Center, UCLAApr 23, 2013- -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 09, 2018The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 06, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Benign
-0.0089
T
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.077
T;.;T
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T;D;T
M_CAP
Pathogenic
0.46
D
MetaRNN
Uncertain
0.62
D;D;D
MetaSVM
Benign
-0.46
T
MutationAssessor
Uncertain
2.8
.;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.77
T
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
D
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.

Other links and lift over

dbSNP: rs765417606; hg19: chrX-70344113; COSMIC: COSV100376703; COSMIC: COSV100376703; API