X-71118787-C-A

Variant names:

• chrX-71118787-C-A
• rs1018272698
• NM_005120.3:c.33C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005120.3(MED12):​c.33C>A​(p.His11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H11H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 20)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.40
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12217063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.33C>A	p.His11Gln	missense_variant	Exon 1 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.33C>A	p.His11Gln	missense_variant	Exon 1 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MED12 c.33C>A (p.His11Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 176433 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.33C>A in individuals affected with MED12-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1718535). Based on the evidence outlined above, the variant was classified as uncertain significance. -

FG syndrome Uncertain:1

Jan 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MED12 protein function. ClinVar contains an entry for this variant (Variation ID: 1718535). This variant has not been reported in the literature in individuals affected with MED12-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 11 of the MED12 protein (p.His11Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.30	.;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N
PhyloP100		3.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.15
Sift	Benign	0.39	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.054	B;B
Vest4		0.21
MutPred		0.22		Gain of disorder (P = 0.0373);Gain of disorder (P = 0.0373);
MVP		0.53
MPC		1.0
ClinPred		0.78	D
GERP RS		4.1
PromoterAI		0.042	Neutral
Varity_R		0.33
gMVP		0.78
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs1018272698; hg19: chrX-70338637;