Genetic Variant NM_005120.3:c.4665G>T (chrX-71134404-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_005120.3(MED12):c.4665G>T(p.Thr1555Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 110,211 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. Synonymous variant affecting the same amino acid position (i.e. T1555T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

MED12
NM_005120.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.24

Publications

0 publications found

Variant links:

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)

MED12 links:

ENSG00000228427 (HGNC:):

ENSG00000228427 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP7

Synonymous conserved (PhyloP=-5.24 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4665G>T	p.Thr1555Thr	synonymous_variant	Exon 34 of 45	ENST00000374080.8	NP_005111.2	Q93074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.4665G>T	p.Thr1555Thr	synonymous_variant	Exon 34 of 45	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.00000907

AC:

AN:

110211

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1057745

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342343

African (AFR)

AF:

0.00

AC:

AN:

25150

American (AMR)

AF:

0.00

AC:

AN:

29515

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18669

East Asian (EAS)

AF:

0.00

AC:

AN:

27675

South Asian (SAS)

AF:

0.00

AC:

AN:

50115

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38233

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4061

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819753

Other (OTH)

AF:

0.00

AC:

AN:

44574

GnomAD4 genome

AF:

0.00000907

AC:

AN:

110211

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32467

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30186

American (AMR)

AF:

0.00

AC:

AN:

10367

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3504

South Asian (SAS)

AF:

0.00

AC:

AN:

2555

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5791

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52766

Other (OTH)

AF:

0.00

AC:

AN:

1481

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.46

(source)

DANN

Benign

0.67

PhyloP100

-5.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over