X-71130195-G-T

Variant names:

• chrX-71130195-G-T
• rs201044355
• NM_005120.3:c.4028G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000374080.8(MED12):​c.4028G>T​(p.Arg1343Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000916 in 1,091,863 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1343H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: MED12 ENST00000374080.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• 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)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3598842).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374080.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.4028G>T	p.Arg1343Leu	missense	Exon 28 of 45	NP_005111.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.4028G>T	p.Arg1343Leu	missense	Exon 28 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.4028G>T	p.Arg1343Leu	missense	Exon 28 of 45	ENSP00000363215.2
	MED12	ENST00000690145.1		c.4028G>T	p.Arg1343Leu	missense	Exon 28 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091863 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 358175

African (AFR) AF: 0.00 AC: 0 AN: 26267

American (AMR) AF: 0.00 AC: 0 AN: 34757

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19277

East Asian (EAS) AF: 0.00 AC: 0 AN: 29963

South Asian (SAS) AF: 0.00 AC: 0 AN: 53028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40159

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3522

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839099

Other (OTH) AF: 0.00 AC: 0 AN: 45791

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.44
Sift	Benign	0.71	T
Sift4G	Benign	0.15	T
Polyphen		0.15	B
Vest4		0.58
MutPred		0.31		Loss of MoRF binding (P = 0.0549)
MVP		1.0
MPC		1.8
ClinPred		0.81	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.49
gMVP		0.65
Mutation Taster		=60/40	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: rs201044355; hg19: chrX-70350045;