X-71119648-C-T

Position:

• chrX-71119648-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005120.3(MED12):​c.205-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,195,049 control chromosomes in the GnomAD database, including 36,042 homozygotes. There are 107,131 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 0.22 (2609 hom., 7062 hem., cov: 23)
  • Exomes 𝑓: 0.29 (33433 hom. 100069 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.375

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-71119648-C-T is Benign according to our data. Variant chrX-71119648-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.205-38C>T		intron_variant		ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.205-38C>T		intron_variant		1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 24462 AN: 111785 Hom.: 2611 Cov.: 23 AF XY: 0.208 AC XY: 7059 AN XY: 34003

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.00279

Gnomad SAS AF: 0.0931

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.457

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.266

GnomAD3 exomes AF: 0.221 AC: 37402 AN: 169442 Hom.: 3667 AF XY: 0.223 AC XY: 12675 AN XY: 56748

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.00137

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.288 AC: 311631 AN: 1083212 Hom.: 33433 Cov.: 30 AF XY: 0.286 AC XY: 100069 AN XY: 350490

Gnomad4 AFR exome AF: 0.0526

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.000964

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.219 AC: 24454 AN: 111837 Hom.: 2609 Cov.: 23 AF XY: 0.207 AC XY: 7062 AN XY: 34065

Gnomad4 AFR AF: 0.0557

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.00280

Gnomad4 SAS AF: 0.0941

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.264

Alfa AF: 0.214 Hom.: 1815

Bravo AF: 0.208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

X-linked intellectual disability with marfanoid habitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

FG syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Blepharophimosis - intellectual disability syndrome, MKB type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12850852; hg19: chrX-70339498; COSMIC: COSV61340521;