rs5030617

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005120.3(MED12):c.3354+27G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,207,848 control chromosomes in the GnomAD database, including 7,017 homozygotes. There are 51,121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1078 hom., 4491 hem., cov: 21)

Exomes 𝑓: 0.12 ( 5939 hom. 46630 hem. )

Consequence

MED12
NM_005120.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.16

Publications

5 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-71128467-G-C is Benign according to our data. Variant chrX-71128467-G-C is described in ClinVar as Benign. ClinVar VariationId is 259636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.3354+27G>C		intron_variant	Intron 23 of 44	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.3354+27G>C		intron_variant	Intron 23 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

16520

AN:

110103

Hom.:

1075

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.0234

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.0906

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.134

GnomAD2 exomes

AF:

0.138

AC:

24941

AN:

181332

AF XY:

0.142

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.0933

Gnomad EAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.124

AC:

136413

AN:

1097691

Hom.:

5939

Cov.:

AF XY:

0.128

AC XY:

46630

AN XY:

363125

show subpopulations

African (AFR)

AF:

0.240

AC:

6324

AN:

26392

American (AMR)

AF:

0.103

AC:

3623

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.0932

AC:

1807

AN:

19380

East Asian (EAS)

AF:

0.116

AC:

3505

AN:

30201

South Asian (SAS)

AF:

0.227

AC:

12309

AN:

54137

European-Finnish (FIN)

AF:

0.118

AC:

4756

AN:

40294

Middle Eastern (MID)

AF:

0.121

AC:

483

AN:

4003

European-Non Finnish (NFE)

AF:

0.116

AC:

97425

AN:

842010

Other (OTH)

AF:

0.134

AC:

6181

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4971

9943

14914

19886

24857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3798

7596

11394

15192

18990

<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:

0.150

AC:

16534

AN:

110157

Hom.:

1078

Cov.:

AF XY:

0.138

AC XY:

4491

AN XY:

32441

show subpopulations

African (AFR)

AF:

0.237

AC:

7131

AN:

30104

American (AMR)

AF:

0.110

AC:

1143

AN:

10431

Ashkenazi Jewish (ASJ)

AF:

0.0906

AC:

239

AN:

2637

East Asian (EAS)

AF:

0.123

AC:

431

AN:

3495

South Asian (SAS)

AF:

0.209

AC:

536

AN:

2560

European-Finnish (FIN)

AF:

0.107

AC:

625

AN:

5829

Middle Eastern (MID)

AF:

0.125

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.117

AC:

6172

AN:

52702

Other (OTH)

AF:

0.143

AC:

214

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

498

997

1495

1994

2492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.131

Hom.:

1054

Bravo

AF:

0.154

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked intellectual disability with marfanoid habitus

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FG syndrome 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Blepharophimosis - intellectual disability syndrome, MKB type

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.68

(source)

DANN

Benign

0.54

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over