NM_005120.3:c.4147G>A

Variant names:

• chrX-71132100-G-A
• rs863223696
• NM_005120.3:c.4147G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005120.3(MED12):​c.4147G>A​(p.Ala1383Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 O:1
• Conservation: PhyloP100: 9.72
• Publications: 14 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)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828
• PP5: Variant X-71132100-G-A is Pathogenic according to our data. Variant chrX-71132100-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213624.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4147G>A	p.Ala1383Thr	missense_variant	Exon 30 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.4147G>A	p.Ala1383Thr	missense_variant	Exon 30 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000892 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Blepharophimosis - intellectual disability syndrome, MKB type Pathogenic:1 Uncertain:1

Apr 03, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: Missense variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.51 (damaging >=0.6, benign <0.4), 3Cnet: 0.14 (damaging >=0.6, benign <0.15)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000213624 /PMID: 26338144). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 36271811). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Aug 28, 2020

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FG syndrome Pathogenic:1

Sep 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MED12 protein function. ClinVar contains an entry for this variant (Variation ID: 213624). This missense change has been observed in individual(s) with clinical features of MED12-related conditions (PMID: 26338144, 36271811). In at least one individual the variant was observed to be de novo. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1383 of the MED12 protein (p.Ala1383Thr).

not provided Pathogenic:1

Oct 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31536828, 26338144, 16700052, 17334363, 26273451, 25644381, 23395478, 24039113, 20970104, 20507344, 17369503, 20301719, 17036352, 10405444, 8279489, 31322785, 30729724, 33057194, 36066546, 36271811, 35982159)

Inborn genetic diseases Uncertain:1

May 08, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FG syndrome 1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Reported in male sibs with nonspecific intellectual disability

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;.;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.0	.;M;M
PhyloP100		9.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.0	.;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.84
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.79
gMVP		0.75
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs863223696; hg19: chrX-70351950; COSMIC: COSV61349273; COSMIC: COSV61349273;