rs1556338747

chrX-71136347-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005120.3(MED12):c.5092G>A(p.Ala1698Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MED12

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.5092G>A	p.Ala1698Thr	missense_variant	37/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.5092G>A	p.Ala1698Thr	missense_variant	37/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2017

Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
REVEL	Uncertain	0.43
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.97	D;P;D
Vest4		0.58
MutPred		0.27		.;Gain of phosphorylation at A1698 (P = 0.0524);Gain of phosphorylation at A1698 (P = 0.0524);
MVP		0.96
MPC		1.6
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.69
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1556338747; hg19: chrX-70356197;