chrX-71137228-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_005120.3(MED12):c.5593A>G(p.Met1865Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,209,899 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000037 ( 0 hom. 15 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 1.76

Publications

2 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09391013).

BP6

Variant X-71137228-A-G is Benign according to our data. Variant chrX-71137228-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000627 (7/111658) while in subpopulation AMR AF = 0.0000946 (1/10572). AF 95% confidence interval is 0.0000256. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 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.5593A>G	p.Met1865Val	missense	Exon 39 of 45	NP_005111.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MED12	ENST00000374080.8	TSL:1 MANE Select	c.5593A>G	p.Met1865Val	missense	Exon 39 of 45	ENSP00000363193.3
MED12	ENST00000374102.6	TSL:1	c.5593A>G	p.Met1865Val	missense	Exon 39 of 45	ENSP00000363215.2
MED12	ENST00000690145.1		c.5593A>G	p.Met1865Val	missense	Exon 39 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

111658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000946

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:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000553

AC:

AN:

180763

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:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000373

AC:

AN:

1098241

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363597

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26402

American (AMR)

AF:

0.0000284

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.0000993

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

842127

Other (OTH)

AF:

0.0000217

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000627

AC:

AN:

111658

Hom.:

Cov.:

AF XY:

0.0000886

AC XY:

AN XY:

33842

show subpopulations

African (AFR)

AF:

0.0000651

AC:

AN:

30722

American (AMR)

AF:

0.0000946

AC:

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6073

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000754

AC:

AN:

53025

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

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)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.30

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.80

M_CAP

Benign

0.020

MetaRNN

Benign

0.094

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.8

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

REVEL

Benign

0.12

Sift

Uncertain

0.016

Sift4G

Benign

0.10

Polyphen

0.0

Vest4

0.18

MutPred

0.30

Loss of catalytic residue at V1861 (P = 0.0373)

MVP

0.65

MPC

0.71

ClinPred

0.033

GERP RS

1.9

Varity_R

0.35

gMVP

0.21

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over