rs80338759

Positions:

• chrX-71127931-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP5_Moderate BP4

The NM_005120.3(MED12):​c.3020A>G​(p.Asn1007Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N1007N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4 O:1
• Conservation: PhyloP100: 8.93

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 Uncertain_significance. Variant got 4 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-71127931-A-G is Pathogenic according to our data. Variant chrX-71127931-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11521.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71127931-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.27516586). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.3020A>G	p.Asn1007Ser	missense_variant	22/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.3020A>G	p.Asn1007Ser	missense_variant	22/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability with marfanoid habitus Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.3020A>G(p.Asn1007Ser) in MED12 gene has been reported previously in homozygous state in individuals with Nonsyndromic X-linked intellectual deficiency, Lujan syndrome (Bouazzi H, et al., 2015, Schwartz CE, et al., 2007). The c.3020A>G variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. However, experimental studies on the pathogenicity of the variant are not available. The amino acid Asparagine at position 1007 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen-Benign, SIFT-Tolerated and Mutation Taster-Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid p.Asn1007Ser in MED12 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 08, 2008	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

FG syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

Recurrent variant in persons with Lujan syndrome -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.071	T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.5	.;L;L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.25
Sift	Benign	0.74	.;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0050	B;B;B
Vest4		0.60
MutPred		0.64		.;Loss of catalytic residue at N1007 (P = 0.0205);Loss of catalytic residue at N1007 (P = 0.0205);
MVP		0.87
MPC		1.2
ClinPred		0.74	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80338759; hg19: chrX-70347781;