X-71127367-C-T

Variant names:

• chrX-71127367-C-T
• rs80338758
• NM_005120.3:c.2881C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_005120.3(MED12):​c.2881C>T​(p.Arg961Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000250607: Published functional studies demonstrate prevention of normal suppression of GLI3, resulting in enhanced SHH signaling pathway activation (Zhou et al., 2012)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R961R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 5.85
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• FG syndrome 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• MED12-related intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000250607: Published functional studies demonstrate prevention of normal suppression of GLI3, resulting in enhanced SHH signaling pathway activation (Zhou et al., 2012); SCV001584353: Experimental studies have shown that this missense change affects MED12 function (PMID: 23091001).; SCV001445037: Functional analyses demonstrated that the p.R961W alteration in patient-derived cells showed increased signaling and/or activation of downstream genes and this dysregulated signaling contributes to the phenotypes of patients with FG and Lujan syndromes (Zhou, 2012; Donnio, 2017).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71127367-C-T is Pathogenic according to our data. Variant chrX-71127367-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.2881C>T	p.Arg961Trp	missense	Exon 21 of 45	NP_005111.2	Q93074-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.2881C>T	p.Arg961Trp	missense	Exon 21 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.2881C>T	p.Arg961Trp	missense	Exon 21 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.2881C>T	p.Arg961Trp	missense	Exon 21 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	FG syndrome 1 (5)
4	-	-	not provided (4)
2	-	-	Blepharophimosis - intellectual disability syndrome, MKB type (2)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	FG syndrome (1)
1	-	-	Imperforate anus;C0175754:Corpus callosum, agenesis of;C0424503:Abnormal facial shape;C0426891:Broad thumb;C0557874:Global developmental delay;C3714756:Intellectual disability (1)
1	-	-	Intellectual disability (1)
1	-	-	MED12-related disorder (1)
1	-	-	X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type;C5399762:FG syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.1	L
PhyloP100		5.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.67		Loss of disorder (P = 0.015)
MVP		0.96
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.83
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80338758; hg19: chrX-70347217; COSMIC: COSV61343293; COSMIC: COSV61343293;