rs5030619

chrX-71130097-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005120.3(MED12):c.3930A>C(p.Pro1310=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,206,739 control chromosomes in the GnomAD database, including 36,144 homozygotes. There are 108,959 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (2601 hom., 7027 hem., cov: 24)
  • Exomes 𝑓: 0.29 (33543 hom. 101932 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.08

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-71130097-A-C is Benign according to our data. Variant chrX-71130097-A-C is described in ClinVar as [Benign]. Clinvar id is 95248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71130097-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• 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	UniProt
MED12	NM_005120.3	c.3930A>C	p.Pro1310=	synonymous_variant	28/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.3930A>C	p.Pro1310=	synonymous_variant	28/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.218 AC: 24407 AN: 111958 Hom.: 2603 Cov.: 24 AF XY: 0.206 AC XY: 7024 AN XY: 34148

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0922

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.269

GnomAD3 exomes AF: 0.220 AC: 38184 AN: 173323 Hom.: 3695 AF XY: 0.223 AC XY: 13321 AN XY: 59861

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.00143

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.287 AC: 314096 AN: 1094726 Hom.: 33543 Cov.: 34 AF XY: 0.283 AC XY: 101932 AN XY: 360392

Gnomad4 AFR exome AF: 0.0516

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.000961

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.218 AC: 24399 AN: 112013 Hom.: 2601 Cov.: 24 AF XY: 0.205 AC XY: 7027 AN XY: 34213

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.0932

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.267

Alfa AF: 0.292 Hom.: 13521

Bravo AF: 0.207

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

X-linked intellectual disability with marfanoid habitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2014

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 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

FG syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	-0.79
Cadd	Benign	1.7
Dann	Benign	0.69

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: rs5030619; hg19: chrX-70349947; COSMIC: COSV61340557; COSMIC: COSV61340557;