rs775072642

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP6_ModerateBS2

The NM_005120.3(MED12):​c.380C>T​(p.Thr127Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000638 in 1,097,852 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

1
5
11

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.10
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 -5 ACMG points.

PP2
Missense variant in the MED12 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 108 curated benign missense variants. Gene score misZ: 6.5797 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
BP6
Variant X-71119861-C-T is Benign according to our data. Variant chrX-71119861-C-T is described in ClinVar as [Benign]. Clinvar id is 240097.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED12NM_005120.3 linkc.380C>T p.Thr127Met missense_variant Exon 3 of 45 ENST00000374080.8 NP_005111.2 Q93074-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED12ENST00000374080.8 linkc.380C>T p.Thr127Met missense_variant Exon 3 of 45 1 NM_005120.3 ENSP00000363193.3 Q93074-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.0000166
AC:
3
AN:
180669
Hom.:
0
AF XY:
0.0000451
AC XY:
3
AN XY:
66549
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000740
Gnomad SAS exome
AF:
0.000106
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000638
AC:
7
AN:
1097852
Hom.:
0
Cov.:
32
AF XY:
0.00000826
AC XY:
3
AN XY:
363210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000331
Gnomad4 SAS exome
AF:
0.0000370
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000475
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
ExAC
AF:
0.0000331
AC:
4

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

FG syndrome Benign:1
Jan 24, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.062
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
.;T
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Uncertain
0.47
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.20
N;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.22
Sift
Benign
0.21
T;T
Sift4G
Benign
0.27
T;T
Polyphen
1.0
D;D
Vest4
0.15
MVP
0.92
MPC
1.5
ClinPred
0.34
T
GERP RS
4.9
Varity_R
0.24
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs775072642; hg19: chrX-70339711; COSMIC: COSV100376700; API