rs200301833

chrX-71119486-ACT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005120.3(MED12):c.204+12_204+13del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,171,464 control chromosomes in the GnomAD database, including 6 homozygotes. There are 351 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (2 hom., 175 hem., cov: 22)
  • Exomes 𝑓: 0.00062 (4 hom. 176 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.444

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 -16 ACMG points.

• BP6: Variant X-71119486-ACT-A is Benign according to our data. Variant chrX-71119486-ACT-A is described in ClinVar as [Benign]. Clinvar id is 213613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71119486-ACT-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0056 (626/111804) while in subpopulation AFR AF= 0.0197 (605/30765). AF 95% confidence interval is 0.0184. There are 2 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.204+12_204+13del		intron_variant		ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.204+12_204+13del		intron_variant		1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.00558 AC: 624 AN: 111751 Hom.: 2 Cov.: 22 AF XY: 0.00513 AC XY: 174 AN XY: 33939

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

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: 0.00

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.00145 AC: 206 AN: 142122 Hom.: 0 AF XY: 0.000946 AC XY: 42 AN XY: 44418

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.000428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000171

Gnomad OTH exome AF: 0.000265

GnomAD4 exome AF: 0.000618 AC: 655 AN: 1059660 Hom.: 4 AF XY: 0.000525 AC XY: 176 AN XY: 335032

Gnomad4 AFR exome AF: 0.0215

Gnomad4 AMR exome AF: 0.000532

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000983

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00560 AC: 626 AN: 111804 Hom.: 2 Cov.: 22 AF XY: 0.00515 AC XY: 175 AN XY: 34002

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.00256 Hom.: 11

Bravo AF: 0.00621

Asia WGS AF: 0.00159 AC: 4 AN: 2522

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant was found in TAAD,TAADV2-1 -

FG syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs200301833; hg19: chrX-70339336;