rs766485358

Positions:

chrX-71123658-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_005120.3(MED12):c.1682C>T(p.Pro561Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000298 in 1,206,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000029 ( 0 hom. 11 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED12. . Gene score misZ: 6.5797 (greater than the threshold 3.09). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 108 curated benign missense variants. GenCC has associacion of the gene with MED12-related intellectual disability syndrome, X-linked intellectual disability with marfanoid habitus, blepharophimosis - intellectual disability syndrome, MKB type, FG syndrome 1, cholestasis-pigmentary retinopathy-cleft palate syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.062033206).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000358 (4/111587) while in subpopulation AMR AF= 0.0000952 (1/10506). AF 95% confidence interval is 0.000015. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.1682C>T	p.Pro561Leu	missense_variant	12/45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.1682C>T	p.Pro561Leu	missense_variant	12/45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0000358

AC:

AN:

111587

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33757

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000952

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000228

AC:

AN:

175798

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

62010

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000754

Gnomad SAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1095220

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

360680

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000517

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.0000373

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000309

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000358

AC:

AN:

111587

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33757

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000952

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2017	The P561L variant in the MED12 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P561L variant is observed in 1/5278 (0.019%) alleles from individuals of East Asian background, including one hemizygous individual, in the ExAC dataset (Lek et al., 2016. The P561L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P561L as a variant of uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.1682C>T (p.P561L) alteration is located in exon 12 (coding exon 12) of the MED12 gene. This alteration results from a C to T substitution at nucleotide position 1682, causing the proline (P) at amino acid position 561 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

FG syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.046

T;.;T

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.062

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.12

.;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.9

.;N;N

REVEL

Benign

0.053

Sift

Benign

0.090

.;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.16

MutPred

0.18

.;Loss of glycosylation at P561 (P = 0.0203);Loss of glycosylation at P561 (P = 0.0203);

MVP

0.14

MPC

0.93

ClinPred

0.15

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over