rs1556337063

Variant names:

• chrX-71130051-G-A
• rs1556337063
• NM_005120.3:c.3884G>A
• MED12 p.Arg1295His

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3 PM2 PM5 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004268121: Experimental studies have shown that this missense change affects MED12 function (PMID:28369444).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1295C) has been classified 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 criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.49
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004268121: Experimental studies have shown that this missense change affects MED12 function (PMID: 28369444).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71130050-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 213640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant X-71130051-G-A is Pathogenic according to our data. Variant chrX-71130051-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 521365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3840931). . Strength limited to SUPPORTING due to the PP5.

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.3884G>A	p.Arg1295His	missense	Exon 28 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.3884G>A	p.Arg1295His	missense	Exon 28 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.3884G>A	p.Arg1295His	missense	Exon 28 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.3926G>A	p.Arg1309His	missense	Exon 28 of 45	ENSP00000608071.1

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

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 34957

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 53384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40353

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840734

Other (OTH) AF: 0.00 AC: 0 AN: 46011

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	FG syndrome (1)
1	-	-	not provided (1)
-	-	-	FG syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.63	N
PhyloP100		5.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.61
Sift	Benign	0.20	T
Sift4G	Benign	0.32	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.82
Mutation Taster		=29/71	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1556337063;

hg19: chrX-70349901;

COSMIC: COSV61343827;

COSMIC: COSV61343827;