X-71136968-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005120.3(MED12):c.5490A>G(p.Thr1830Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,206,231 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1830T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000026 ( 0 hom. 9 hem. )

Consequence

MED12
NM_005120.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.681

Publications

0 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: G2P, Labcorp Genetics (formerly Invitae), 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
blepharophimosis - intellectual disability syndrome, MKB type
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.008).

BP6

Variant X-71136968-A-G is Benign according to our data. Variant chrX-71136968-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1747857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.681 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000265 (29/1096267) while in subpopulation EAS AF = 0.0000663 (2/30178). AF 95% confidence interval is 0.0000171. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.5490A>G	p.Thr1830Thr	synonymous	Exon 38 of 45	NP_005111.2	Q93074-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MED12	ENST00000374080.8	TSL:1 MANE Select	c.5490A>G	p.Thr1830Thr	synonymous	Exon 38 of 45	ENSP00000363193.3	Q93074-1
MED12	ENST00000374102.6	TSL:1	c.5490A>G	p.Thr1830Thr	synonymous	Exon 38 of 45	ENSP00000363215.2	Q93074-2
MED12	ENST00000938012.1		c.5532A>G	p.Thr1844Thr	synonymous	Exon 38 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes

AF:

0.0000182

AC:

AN:

109964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000173

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000511

AC:

AN:

176067

AF XY:

0.0000799

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:

0.0000707

Gnomad NFE exome

AF:

0.0000885

Gnomad OTH exome

AF:

0.000231

GnomAD4 exome

AF:

0.0000265

AC:

AN:

1096267

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361845

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26386

American (AMR)

AF:

0.00

AC:

AN:

35121

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19355

East Asian (EAS)

AF:

0.0000663

AC:

AN:

30178

South Asian (SAS)

AF:

0.00

AC:

AN:

53890

European-Finnish (FIN)

AF:

0.0000253

AC:

AN:

39541

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

841621

Other (OTH)

AF:

0.0000869

AC:

AN:

46040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000182

AC:

AN:

109964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30134

American (AMR)

AF:

0.00

AC:

AN:

10340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2631

East Asian (EAS)

AF:

0.00

AC:

AN:

3479

South Asian (SAS)

AF:

0.00

AC:

AN:

2556

European-Finnish (FIN)

AF:

0.000173

AC:

AN:

5795

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52640

Other (OTH)

AF:

0.00

AC:

AN:

1477

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial thoracic aortic aneurysm and aortic dissection (1)

FG syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.2

(source)

DANN

Benign

0.54

PhyloP100

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over