X-71118549-A-G

Variant names:

• chrX-71118549-A-G
• rs11796153
• ENST00000692304.1:c.-206A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000692304.1(MED12):​c.-206A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (12781 hom., 17441 hem., cov: 22)
  • Exomes 𝑓: 0.47 (25492 hom. 51828 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 ENST00000692304.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.46
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• FG syndrome 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• MED12-related intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-71118549-A-G is Benign according to our data. Variant chrX-71118549-A-G is described in ClinVar as [Benign]. Clinvar id is 670932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.-206A>G		upstream_gene_variant		ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.-206A>G		upstream_gene_variant		1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.550 AC: 60675 AN: 110285 Hom.: 12781 Cov.: 22

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.626

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.574

GnomAD4 exome AF: 0.471 AC: 156103 AN: 331561 Hom.: 25492 Cov.: 3 AF XY: 0.470 AC XY: 51828 AN XY: 110233

African (AFR) AF: 0.751 AC: 7724 AN: 10288

American (AMR) AF: 0.606 AC: 11385 AN: 18785

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 6089 AN: 10572

East Asian (EAS) AF: 0.323 AC: 7356 AN: 22744

South Asian (SAS) AF: 0.476 AC: 13477 AN: 28313

European-Finnish (FIN) AF: 0.391 AC: 8697 AN: 22218

Middle Eastern (MID) AF: 0.588 AC: 824 AN: 1402

European-Non Finnish (NFE) AF: 0.458 AC: 90480 AN: 197459

Other (OTH) AF: 0.509 AC: 10071 AN: 19780

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.550 AC: 60731 AN: 110341 Hom.: 12781 Cov.: 22 AF XY: 0.536 AC XY: 17441 AN XY: 32567

African (AFR) AF: 0.751 AC: 22757 AN: 30284

American (AMR) AF: 0.601 AC: 6288 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1502 AN: 2630

East Asian (EAS) AF: 0.325 AC: 1129 AN: 3472

South Asian (SAS) AF: 0.458 AC: 1179 AN: 2572

European-Finnish (FIN) AF: 0.383 AC: 2231 AN: 5832

Middle Eastern (MID) AF: 0.636 AC: 136 AN: 214

European-Non Finnish (NFE) AF: 0.461 AC: 24304 AN: 52706

Other (OTH) AF: 0.581 AC: 876 AN: 1507

Alfa AF: 0.513 Hom.: 58702

Bravo AF: 0.575

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.14
DANN	Benign	0.69
PhyloP100		-3.5
PromoterAI		0.035	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11796153; hg19: chrX-70338399;