rs1556337063

Positions:

• chrX-71130051-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2 PP2 PP5_Very_Strong BP4

The NM_005120.3(MED12):​c.3884G>A​(p.Arg1295His) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,459 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.49

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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.
• PP5: Variant X-71130051-G-A is Pathogenic according to our data. Variant chrX-71130051-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71130051-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3840931). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MED12	NM_005120.3	c.3884G>A	p.Arg1295His	missense_variant	28/45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.3884G>A	p.Arg1295His	missense_variant	28/45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095459 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361059

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2024

The c.3884G>A (p.R1295H) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution at nucleotide position 3884, causing the arginine (R) at amino acid position 1295 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation, has been identified in individuals with features consistent with MED12-related disorder, and segregated with disease in at least one family (Donnio, 2017; Srivastava, 2019; Maia, 2023; Callier, 2013; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2021

Segregated in an affected hemizygous brother in one family, and a heterozygous mother with moderate learning difficulties, skeletal and dysmorphic features, mitral valve prolapse, and skewed X-inactivation in another family (Callier et al., 2013; Donnio et al., 2017; Srivastava et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; A different missense change at this residue (R1295C) has been reported in the published literature in association with MED12-related disorders (Hu et al., 2016; Charzewska et al., 2018; Rubinato et al., 2019); This variant is associated with the following publications: (PMID: 31536828, 25644381, 33925166, 23506379, 28369444, 30729724) -

FG syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1295 of the MED12 protein (p.Arg1295His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked recessive MED12-related conditions (PMID: 23506379, 28369444, 30729724, 36271811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 521365). 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 not expected to disrupt MED12 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MED12 function (PMID: 28369444). For these reasons, this variant has been classified as Pathogenic. -

FG syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

Reported in persons with nonspecific intellectual disability and features of Lujan syndrome and in male sibs with features of FG syndrome type 1 and Lujan syndrome -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.63	.;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	.;N;D
REVEL	Uncertain	0.61
Sift	Benign	0.20	.;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.90	P;P;B
Vest4		0.30
MutPred		0.59		.;Loss of ubiquitination at K1298 (P = 0.0907);Loss of ubiquitination at K1298 (P = 0.0907);
MVP		0.99
MPC		1.8
ClinPred		0.83	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1556337063; hg19: chrX-70349901; COSMIC: COSV61343827; COSMIC: COSV61343827;