rs1556334519

Positions:

• chrX-71121602-G-A
• chrX-71121602-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_005120.3(MED12):​c.887G>A​(p.Arg296Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.60

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MED12. . Gene score misZ 6.5797 (greater than the threshold 3.09). GenCC has associacion of gene with MED12-related intellectual disability syndrome, X-linked intellectual disability with marfanoid habitus, blepharophimosis - intellectual disability syndrome, MKB type, FG syndrome 1, cholestasis-pigmentary retinopathy-cleft palate syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant X-71121602-G-A is Pathogenic according to our data. Variant chrX-71121602-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71121602-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.887G>A	p.Arg296Gln	missense_variant	7/45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.887G>A	p.Arg296Gln	missense_variant	7/45	1	NM_005120.3	ENSP00000363193	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blepharophimosis - intellectual disability syndrome, MKB type Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Oct 02, 2023	This missense variant is absent from controls (PM2), and mRNA level analysis showed splicing variant causing 14 aminoacids inframe deletion in LCEWAV domain (NM_005120.3:r.847_888del ) (PM4) at the same time of missense effect p.Arg296Gln. This variant was cosegregated with both affected brothers and carrier mother (PP1), and symptoms were consistent with X-linked Ohdo syndrome (PP4). Multiple lines of computational evidence support a deleterious effect as CADD phred score is 31 (PP3), also previously reported as likely-pathogenic in ClinVae (PP5). This variant It is judged to be likely-pathogenic according to ACMG Guidelines, 2015. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Sep 21, 2023	PS4, PM2, PP3, PP5 - The variant has been reported in ClinVar by other laboratories (Variation ID 1069251). This missense change has been observed in individual(s) with MED12 X-linked recessive associated conditions (PMID: 34573309). Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. -

FG syndrome 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Reported in persons with X-linked Ohdo syndrome and nonspecific intellectual disability -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000522111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2017

- -

FG syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MED12 protein function. ClinVar contains an entry for this variant (Variation ID: 522111). This missense change has been observed in individual(s) with MED12 X-linked recessive associated conditions (PMID: 27500536, 28794916, 34573309). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 296 of the MED12 protein (p.Arg296Gln). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20301719, 28794916, 31536828, 34573309, 27500536, 27620904, 32682435) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.076	T;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	.;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.56
MutPred		0.73		.;Loss of MoRF binding (P = 0.0252);Loss of MoRF binding (P = 0.0252);
MVP		0.79
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556334519; hg19: chrX-70341452;