rs200663107

Variant names:

• chrX-71137346-C-T
• rs200663107
• NM_005120.3:c.5711C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005120.3(MED12):​c.5711C>T​(p.Ala1904Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,209,731 control chromosomes in the GnomAD database, including 5 homozygotes. There are 413 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1904A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., 26 hem., cov: 22)
  • Exomes 𝑓: 0.0011 (5 hom. 387 hem.)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 3.18
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae), 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cholestasis-pigmentary retinopathy-cleft palate syndrome

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000228427 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003823787).
• BP6: Variant X-71137346-C-T is Benign according to our data. Variant chrX-71137346-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000896 (100/111661) while in subpopulation AMR AF = 0.00151 (16/10586). AF 95% confidence interval is 0.000948. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005120.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.5711C>T	p.Ala1904Val	missense	Exon 39 of 45	NP_005111.2	Q93074-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.5711C>T	p.Ala1904Val	missense	Exon 39 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.5711C>T	p.Ala1904Val	missense	Exon 39 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.5753C>T	p.Ala1918Val	missense	Exon 39 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.000896 AC: 100 AN: 111610 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00717

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00200

GnomAD2 exomes AF: 0.00118 AC: 213 AN: 180002 AF XY: 0.00103

Gnomad AFR exome AF: 0.000162

Gnomad AMR exome AF: 0.000658

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000629

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00105 AC: 1156 AN: 1098070 Hom.: 5 Cov.: 32 AF XY: 0.00106 AC XY: 387 AN XY: 363426

African (AFR) AF: 0.000189 AC: 5 AN: 26399

American (AMR) AF: 0.000597 AC: 21 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 195 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54135

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40513

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4135

European-Non Finnish (NFE) AF: 0.00101 AC: 852 AN: 842014

Other (OTH) AF: 0.00145 AC: 67 AN: 46090

GnomAD4 genome AF: 0.000896 AC: 100 AN: 111661 Hom.: 0 Cov.: 22 AF XY: 0.000768 AC XY: 26 AN XY: 33857

African (AFR) AF: 0.000163 AC: 5 AN: 30705

American (AMR) AF: 0.00151 AC: 16 AN: 10586

Ashkenazi Jewish (ASJ) AF: 0.00717 AC: 19 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.00 AC: 0 AN: 2651

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6028

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.00104 AC: 55 AN: 53101

Other (OTH) AF: 0.00197 AC: 3 AN: 1520

Alfa AF: 0.00167 Hom.: 81

Bravo AF: 0.000926

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000603 AC: 2

ESP6500EA AF: 0.00186 AC: 12

ExAC AF: 0.000985 AC: 119

EpiCase AF: 0.00196

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (4)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FG syndrome (1)
-	-	1	MED12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.055
Sift	Benign	0.29	T
Sift4G	Benign	0.52	T
Polyphen		0.088	B
Vest4		0.18
MVP		0.63
MPC		0.79
ClinPred		0.0097	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200663107; hg19: chrX-70357196; COSMIC: COSV100380089;