rs370211858

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.4425A>G(p.Leu1475Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,166,577 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 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 0.000087 ( 0 hom., 5 hem., cov: 21)

Exomes 𝑓: 0.00017 ( 0 hom. 53 hem. )

Consequence

MED12
NM_005120.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.191

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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant X-71132854-A-G is Benign according to our data. Variant chrX-71132854-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 458817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.191 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000873 (9/103081) while in subpopulation NFE AF = 0.0000996 (5/50224). AF 95% confidence interval is 0.0000387. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 5 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.4425A>G	p.Leu1475Leu	synonymous	Exon 32 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.4425A>G	p.Leu1475Leu	synonymous	Exon 32 of 45	ENSP00000363193.3	Q93074-1
MED12	ENST00000374102.6	TSL:1	c.4425A>G	p.Leu1475Leu	synonymous	Exon 32 of 45	ENSP00000363215.2	Q93074-2
MED12	ENST00000938012.1		c.4467A>G	p.Leu1489Leu	synonymous	Exon 32 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes

AF:

0.0000874

AC:

AN:

103028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000702

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000794

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000995

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000880

AC:

AN:

136441

AF XY:

0.0000934

show subpopulations

Gnomad AFR exome

AF:

0.000111

Gnomad AMR exome

AF:

0.0000452

Gnomad ASJ exome

AF:

0.000150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000173

AC:

184

AN:

1063496

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

343266

show subpopulations

African (AFR)

AF:

0.0000387

AC:

AN:

25833

American (AMR)

AF:

0.0000327

AC:

AN:

30537

Ashkenazi Jewish (ASJ)

AF:

0.000320

AC:

AN:

18774

East Asian (EAS)

AF:

0.00

AC:

AN:

29099

South Asian (SAS)

AF:

0.0000197

AC:

AN:

50870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38263

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3743

European-Non Finnish (NFE)

AF:

0.000207

AC:

170

AN:

821624

Other (OTH)

AF:

0.000112

AC:

AN:

44753

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0000873

AC:

AN:

103081

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

28149

show subpopulations

African (AFR)

AF:

0.0000700

AC:

AN:

28578

American (AMR)

AF:

0.00

AC:

AN:

9293

Ashkenazi Jewish (ASJ)

AF:

0.000794

AC:

AN:

2520

East Asian (EAS)

AF:

0.00

AC:

AN:

3263

South Asian (SAS)

AF:

0.00

AC:

AN:

2274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

207

European-Non Finnish (NFE)

AF:

0.0000996

AC:

AN:

50224

Other (OTH)

AF:

0.00

AC:

AN:

1395

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.000174

Hom.:

Bravo

AF:

0.000174

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

FG syndrome (1)

MED12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

3.5

(source)

DANN

Benign

0.65

PhyloP100

0.19

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

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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

Computational scores

Splicing

Publications

Other links and lift over