rs5030617

chrX-71128467-G-C

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.3354+27G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,207,848 control chromosomes in the GnomAD database, including 7,017 homozygotes. There are 51,121 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1078 hom., 4491 hem., cov: 21)
  • Exomes 𝑓: 0.12 (5939 hom. 46630 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-71128467-G-C is Benign according to our data. Variant chrX-71128467-G-C is described in ClinVar as [Benign]. Clinvar id is 259636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.3354+27G>C		intron_variant		ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.3354+27G>C		intron_variant		1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.150 AC: 16520 AN: 110103 Hom.: 1075 Cov.: 21 AF XY: 0.138 AC XY: 4477 AN XY: 32377

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.0234

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0906

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.138 AC: 24941 AN: 181332 Hom.: 1251 AF XY: 0.142 AC XY: 9549 AN XY: 67212

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0933

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.124 AC: 136413 AN: 1097691 Hom.: 5939 Cov.: 33 AF XY: 0.128 AC XY: 46630 AN XY: 363125

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.0932

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.150 AC: 16534 AN: 110157 Hom.: 1078 Cov.: 21 AF XY: 0.138 AC XY: 4491 AN XY: 32441

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0906

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.143

Alfa AF: 0.131 Hom.: 1054

Bravo AF: 0.154

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

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	-0.83
Cadd	Benign	0.68
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5030617; hg19: chrX-70348317; COSMIC: COSV61332975; COSMIC: COSV61332975;