rs201807437

Positions:

• chrX-71128115-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005120.3(MED12):​c.3204C>T​(p.Pro1068=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,206,174 control chromosomes in the GnomAD database, including 1 homozygotes. There are 636 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 0.0011 (0 hom., 34 hem., cov: 22)
  • Exomes 𝑓: 0.0017 (1 hom. 602 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.34

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-71128115-C-T is Benign according to our data. Variant chrX-71128115-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 167284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71128115-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00107 (120/111649) while in subpopulation NFE AF= 0.00192 (102/53094). AF 95% confidence interval is 0.00162. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.3204C>T	p.Pro1068=	synonymous_variant	22/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.3204C>T	p.Pro1068=	synonymous_variant	22/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 120 AN: 111596 Hom.: 0 Cov.: 22 AF XY: 0.00101 AC XY: 34 AN XY: 33792

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00192

Gnomad OTH AF: 0.000669

GnomAD3 exomes AF: 0.00147 AC: 266 AN: 180566 Hom.: 0 AF XY: 0.00135 AC XY: 90 AN XY: 66590

Gnomad AFR exome AF: 0.000242

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000524

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.000673

GnomAD4 exome AF: 0.00175 AC: 1914 AN: 1094525 Hom.: 1 Cov.: 31 AF XY: 0.00167 AC XY: 602 AN XY: 360055

Gnomad4 AFR exome AF: 0.0000380

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.0000517

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000629

Gnomad4 FIN exome AF: 0.00243

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00100

GnomAD4 genome AF: 0.00107 AC: 120 AN: 111649 Hom.: 0 Cov.: 22 AF XY: 0.00100 AC XY: 34 AN XY: 33855

Gnomad4 AFR AF: 0.000163

Gnomad4 AMR AF: 0.000285

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000376

Gnomad4 FIN AF: 0.00116

Gnomad4 NFE AF: 0.00192

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.00167 Hom.: 13

Bravo AF: 0.000971

EpiCase AF: 0.00164

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 12, 2018	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 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

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.7
DANN	Benign	0.66

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: rs201807437; hg19: chrX-70347965;