X-71140797-ACAG-ACAGCAG

Position:

• chrX-71140797-ACAG-ACAGCAG

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_005120.3(MED12):​c.6226_6228dup​(p.Gln2076dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.000409 in 1,201,713 control chromosomes in the GnomAD database, including 1 homozygotes. There are 100 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., 14 hem., cov: 22)
  • Exomes 𝑓: 0.00040 (1 hom. 86 hem.)
• Consequence: MED12 NM_005120.3 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.36

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71140797-A-ACAG is Benign according to our data. Variant chrX-71140797-A-ACAG is described in ClinVar as [Likely_benign]. Clinvar id is 166875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.6226_6228dup	p.Gln2076dup	inframe_insertion	42/45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6226_6228dup	p.Gln2076dup	inframe_insertion	42/45	1	NM_005120.3	ENSP00000363193	P4

Frequencies

GnomAD3 genomes AF: 0.000464 AC: 51 AN: 109909 Hom.: 0 Cov.: 22 AF XY: 0.000431 AC XY: 14 AN XY: 32501

Gnomad AFR AF: 0.0000331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000573

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000248

Gnomad OTH AF: 0.000683

GnomAD3 exomes AF: 0.000790 AC: 133 AN: 168423 Hom.: 0 AF XY: 0.000386 AC XY: 23 AN XY: 59581

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000541

Gnomad SAS exome AF: 0.000277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000945

GnomAD4 exome AF: 0.000403 AC: 440 AN: 1091760 Hom.: 1 Cov.: 33 AF XY: 0.000240 AC XY: 86 AN XY: 358968

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.0000570

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000997

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.0000254

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000464 AC: 51 AN: 109953 Hom.: 0 Cov.: 22 AF XY: 0.000430 AC XY: 14 AN XY: 32555

Gnomad4 AFR AF: 0.0000330

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000575

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000248

Gnomad4 OTH AF: 0.000674

Bravo AF: 0.000495

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2014	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MED12: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2022	See Variant Classification Assertion Criteria. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2017

This alteration is classified as 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 29, 2024

- -

MED12-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs757160341; hg19: chrX-70360647;