X-71132767-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT-CCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTTCTCTT

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.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., 118 hem., cov: 0)

Exomes 𝑓: 0.0099 ( 118 hom. 1792 hem. )

Failed GnomAD Quality Control

Consequence

MED12
NM_005120.3 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.294

Publications

3 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 eas. GnomAd4 allele frequency = 0.0105 (954/90655) while in subpopulation EAS AF = 0.0128 (33/2570). AF 95% confidence interval is 0.0118. There are 19 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3 link	c.4416-35_4416-16dupCTTCTCTTCTCTTCTCTTCT		intron_variant	Intron 31 of 44	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.4416-78_4416-77insCTCTTCTCTTCTCTTCTCTT		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3		Q93074-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

952

AN:

90615

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00166

Gnomad AMR

AF:

0.00980

Gnomad ASJ

AF:

0.0238

Gnomad EAS

AF:

0.0132

Gnomad SAS

AF:

0.00802

Gnomad FIN

AF:

0.0324

Gnomad MID

AF:

0.00952

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00756

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00987

AC:

5552

AN:

562300

Hom.:

118

AF XY:

0.0110

AC XY:

1792

AN XY:

162916

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00169

AC:

AN:

14811

American (AMR)

AF:

0.0104

AC:

225

AN:

21573

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

278

AN:

14163

East Asian (EAS)

AF:

0.0117

AC:

273

AN:

23289

South Asian (SAS)

AF:

0.00771

AC:

266

AN:

34521

European-Finnish (FIN)

AF:

0.0407

AC:

1359

AN:

33363

Middle Eastern (MID)

AF:

0.00677

AC:

AN:

1921

European-Non Finnish (NFE)

AF:

0.00716

AC:

2802

AN:

391322

Other (OTH)

AF:

0.0114

AC:

311

AN:

27337

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

140

280

420

560

700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0105

AC:

954

AN:

90655

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

118

AN XY:

18749

show subpopulations

African (AFR)

AF:

0.00231

AC:

AN:

24623

American (AMR)

AF:

0.0103

AC:

AN:

8074

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

AN:

2315

East Asian (EAS)

AF:

0.0128

AC:

AN:

2570

South Asian (SAS)

AF:

0.00807

AC:

AN:

1610

European-Finnish (FIN)

AF:

0.0324

AC:

124

AN:

3826

Middle Eastern (MID)

AF:

0.00529

AC:

AN:

189

European-Non Finnish (NFE)

AF:

0.0127

AC:

578

AN:

45637

Other (OTH)

AF:

0.00744

AC:

AN:

1210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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.:

352

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 20, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.29

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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