rs201044355

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_005120.3(MED12):c.4028G>A(p.Arg1343His) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,205,105 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000012 ( 0 hom. 2 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.82

Publications

1 publications found

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]

MED12 Gene-Disease associations (from GenCC):

FG syndrome 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
MED12-related intellectual disability syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked intellectual disability with marfanoid habitus
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
blepharophimosis - intellectual disability syndrome, MKB type
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
cholestasis-pigmentary retinopathy-cleft palate syndrome
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MED12 links:

ENSG00000228427 (HGNC:):

ENSG00000228427 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13404664).

BP6

Variant X-71130195-G-A is Benign according to our data. Variant chrX-71130195-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 220794.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.4028G>A	p.Arg1343His	missense	Exon 28 of 45	NP_005111.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MED12	ENST00000374080.8	TSL:1 MANE Select	c.4028G>A	p.Arg1343His	missense	Exon 28 of 45	ENSP00000363193.3
MED12	ENST00000374102.6	TSL:1	c.4028G>A	p.Arg1343His	missense	Exon 28 of 45	ENSP00000363215.2
MED12	ENST00000690145.1		c.4028G>A	p.Arg1343His	missense	Exon 28 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes

AF:

0.0000353

AC:

AN:

113254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000641

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000374

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

170175

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1091851

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

358165

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26267

American (AMR)

AF:

0.00

AC:

AN:

34756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19277

East Asian (EAS)

AF:

0.00

AC:

AN:

29963

South Asian (SAS)

AF:

0.00

AC:

AN:

53024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40159

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3522

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

839092

Other (OTH)

AF:

0.00

AC:

AN:

45791

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000353

AC:

AN:

113254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35388

show subpopulations

African (AFR)

AF:

0.0000641

AC:

AN:

31197

American (AMR)

AF:

0.00

AC:

AN:

10753

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3616

South Asian (SAS)

AF:

0.00

AC:

AN:

2826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000374

AC:

AN:

53448

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000154

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

FG syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.027

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.068

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.14

PhyloP100

5.8

PrimateAI

Uncertain

0.79

PROVEAN

Benign

0.66

REVEL

Uncertain

0.39

Sift

Benign

0.64

Sift4G

Benign

0.37

Polyphen

0.29

Vest4

0.22

MVP

0.99

MPC

1.7

ClinPred

0.21

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.29

gMVP

0.59

Mutation Taster

=65/35

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over