rs765417606

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_005120.3(MED12):c.1849A>G(p.Thr617Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000034 in 1,207,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T617T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000029 ( 0 hom. 10 hem. )

Consequence

MED12
NM_005120.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 8.95

Publications

2 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 -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000815 (9/110489) while in subpopulation AMR AF = 0.000479 (5/10442). AF 95% confidence interval is 0.000188. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.1849A>G	p.Thr617Ala	missense_variant	Exon 13 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8 link	c.1849A>G	p.Thr617Ala	missense_variant	Exon 13 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes

AF:

0.0000815

AC:

AN:

110489

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000479

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:

0.0000759

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000275

AC:

AN:

181757

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000613

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1096741

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

362107

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26373

American (AMR)

AF:

0.000114

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54104

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

840766

Other (OTH)

AF:

0.0000652

AC:

AN:

46047

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000815

AC:

AN:

110489

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

32831

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30326

American (AMR)

AF:

0.000479

AC:

AN:

10442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2621

East Asian (EAS)

AF:

0.00

AC:

AN:

3512

South Asian (SAS)

AF:

0.00

AC:

AN:

2597

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5867

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000759

AC:

AN:

52727

Other (OTH)

AF:

0.00

AC:

AN:

1487

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25326637) -

X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type;C5399762:FG syndrome 1

Pathogenic:1

Apr 23, 2013

UCLA Clinical Genomics Center, UCLA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Aug 09, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T617A variant (also known as c.1849A>G), located in coding exon 13 of the MED12 gene, results from an A to G substitution at nucleotide position 1849. The threonine at codon 617 is replaced by alanine, an amino acid with similar properties. This alteration was identified in an individual with autism, craniofacial dysmorphic features, and it was inherited from his mother (Lee H et al. JAMA, 2014 Nov;312:1880-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. -

FG syndrome

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.0089

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.077

T;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

T;D;T

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.8

.;M;M

PhyloP100

8.9

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.9

.;D;D

REVEL

Uncertain

0.55

Sift

Benign

0.053

.;T;T

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.55

MutPred

0.35

.;Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);

MVP

0.88

MPC

2.0

ClinPred

0.78

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.78

Mutation Taster

=72/28

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over