rs187377817

Positions:

chrX-71122361-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005120.3(MED12):c.1248+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,209,524 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,772 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., 96 hem., cov: 23)

Exomes 𝑓: 0.0048 ( 16 hom. 1676 hem. )

Consequence

MED12
NM_005120.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.172

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant X-71122361-T-C is Benign according to our data. Variant chrX-71122361-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138198.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chrX-71122361-T-C is described in Lovd as [Likely_benign]. Variant chrX-71122361-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00299 (336/112341) while in subpopulation NFE AF= 0.00473 (252/53223). AF 95% confidence interval is 0.00425. There are 0 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 96 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3 linkuse as main transcript	c.1248+15T>C		intron_variant		ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8 linkuse as main transcript	c.1248+15T>C		intron_variant		1	NM_005120.3	P4	Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.00299

AC:

336

AN:

112286

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

AN XY:

34450

show subpopulations

Gnomad AFR

AF:

0.00110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00188

Gnomad ASJ

AF:

0.000378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000733

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00473

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00316

AC:

575

AN:

181756

Hom.:

AF XY:

0.00318

AC XY:

215

AN XY:

67584

show subpopulations

Gnomad AFR exome

AF:

0.000807

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000525

Gnomad FIN exome

AF:

0.00584

Gnomad NFE exome

AF:

0.00458

Gnomad OTH exome

AF:

0.00537

GnomAD4 exome

AF:

0.00481

AC:

5279

AN:

1097183

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

1676

AN XY:

362551

show subpopulations

Gnomad4 AFR exome

AF:

0.000531

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000573

Gnomad4 FIN exome

AF:

0.00503

Gnomad4 NFE exome

AF:

0.00563

Gnomad4 OTH exome

AF:

0.00456

GnomAD4 genome

AF:

0.00299

AC:

336

AN:

112341

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

AN XY:

34515

show subpopulations

Gnomad4 AFR

AF:

0.00110

Gnomad4 AMR

AF:

0.00188

Gnomad4 ASJ

AF:

0.000378

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000735

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.00473

Gnomad4 OTH

AF:

0.00330

Alfa

AF:

0.00324

Hom.:

Bravo

AF:

0.00251

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 21, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FG syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.7

DANN

Benign

0.65

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