rs879255527

Positions:

• chrX-71137791-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005120.3(MED12):​c.5898dup​(p.Ser1967GlnfsTer84) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: MED12 NM_005120.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 5.34

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71137791-G-GC is Pathogenic according to our data. Variant chrX-71137791-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.5898dup	p.Ser1967GlnfsTer84	frameshift_variant	41/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.5898dup	p.Ser1967GlnfsTer84	frameshift_variant	41/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2018

The c.5898dupC variant in the MED12 gene has been reported previously in a family with intellectual disability and dysmorphic features and it is associated with mild to severe symptoms in both males and females (Lesca et al., 2013). The duplication causes a frameshift starting with codon Serine 1967, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 84 of the new reading frame, denoted p.Ser1967GlnfsX84. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, RNA expression studies show that the mutated allele was not degraded by nonsense-mediated RNA decay and induced an additional abnormal isoform due to activation of cryptic splice sites (Lesca et al., 2013). The c.5898dupC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

MED12-related intellectual disability syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The hemizygous p.Ser1967GlnfsTer84 variant in MED12 was identified by our study in two affected members of one family with intellectual disability. The p.Ser1967GlnfsTer84 variant in MED12 has been previously reported in 11 affected members of one family with MED12-related disorder and segregated with disease in this family (PMID: 24039113). This variant has also been reported in ClinVar (Variation ID: 252964) and has been interpreted as likely pathogenic by GeneDx. This variant was absent from large population studies. RT-PCR analysis performed on affected tissue showed that while this variant does not result in nonsense mediated decay, it yields two alternative transcripts: one with a frameshift and the other with an in-frame 75 base pair deletion due to activation of 2 cryptic splice sites in exon 41 (PMID: 24039113). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1967 and leads to a premature termination codon 84 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MED12 gene is an established disease mechanism in MED12-related disorders. In summary, this variant meets criteria to be classified as pathogenic for MED12-related disorders. ACMG/AMP Criteria applied: PVS1_Strong, PS3_Moderate, PM2_Supporting, PP1_Strong (Richards 2015). -

FG syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

Reported in males and females with nonspecific intellectual disability -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs879255527; hg19: chrX-70357641;