rs199469669

Variant names:

• chrX-71119403-G-A
• rs199469669
• NM_005120.3:c.130G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71119403-G-A
• chrX-71119403-G-C
• chrX-71119403-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005120.3(MED12):​c.130G>A​(p.Gly44Ser) 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 other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G44V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: other no assertion criteria provided O:2
• Conservation: PhyloP100: 10.0
• Publications: 78 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.130G>A	p.Gly44Ser	missense_variant	Exon 2 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.130G>A	p.Gly44Ser	missense_variant	Exon 2 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1086618 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 355296

African (AFR) AF: 0.00 AC: 0 AN: 26276

American (AMR) AF: 0.00 AC: 0 AN: 34170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19102

East Asian (EAS) AF: 0.00 AC: 0 AN: 30034

South Asian (SAS) AF: 0.00 AC: 0 AN: 52226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39819

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3901

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835461

Other (OTH) AF: 0.00 AC: 0 AN: 45629

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: other

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Uterine leiomyoma Other:1

-

Rajkovic Lab, University of Pittsburgh

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Angiosarcoma Other:1

May 01, 2016

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing

- 3: Mutations in other consensus cancer genes, not currently considered targetable

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.48		Gain of ubiquitination at K42 (P = 0.3248);Gain of ubiquitination at K42 (P = 0.3248);
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.95
gMVP		0.98
Mutation Taster		=64/36	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: rs199469669; hg19: chrX-70339253; COSMIC: COSV61329567;