rs147354926

Variant names:

• chrX-71137285-G-A
• rs147354926
• NM_005120.3:c.5650G>A

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.5650G>A​(p.Gly1884Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,209,022 control chromosomes in the GnomAD database, including 8 homozygotes. There are 398 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1884G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (5 hom., 184 hem., cov: 23)
  • Exomes 𝑓: 0.00066 (3 hom. 214 hem.)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.793
• Publications: 3 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)

ENSG00000228427 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037756264).
• BP6: Variant X-71137285-G-A is Benign according to our data. Variant chrX-71137285-G-A is described in ClinVar as Benign. ClinVar VariationId is 129593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00615 (687/111703) while in subpopulation AFR AF = 0.0214 (659/30740). AF 95% confidence interval is 0.0201. There are 5 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.5650G>A	p.Gly1884Ser	missense	Exon 39 of 45	NP_005111.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.5650G>A	p.Gly1884Ser	missense	Exon 39 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.5650G>A	p.Gly1884Ser	missense	Exon 39 of 45	ENSP00000363215.2
	MED12	ENST00000690145.1		c.5650G>A	p.Gly1884Ser	missense	Exon 39 of 45	ENSP00000508818.1

Frequencies

GnomAD3 genomes AF: 0.00613 AC: 684 AN: 111651 Hom.: 5 Cov.: 23

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00208

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: 0.00

Gnomad OTH AF: 0.00397

GnomAD2 exomes AF: 0.00187 AC: 338 AN: 180651 AF XY: 0.00130

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000659 AC: 723 AN: 1097319 Hom.: 3 Cov.: 32 AF XY: 0.000590 AC XY: 214 AN XY: 362711

African (AFR) AF: 0.0226 AC: 597 AN: 26389

American (AMR) AF: 0.00139 AC: 49 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4137

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841280

Other (OTH) AF: 0.00130 AC: 60 AN: 46062

GnomAD4 genome AF: 0.00615 AC: 687 AN: 111703 Hom.: 5 Cov.: 23 AF XY: 0.00543 AC XY: 184 AN XY: 33897

African (AFR) AF: 0.0214 AC: 659 AN: 30740

American (AMR) AF: 0.00208 AC: 22 AN: 10571

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6065

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53067

Other (OTH) AF: 0.00392 AC: 6 AN: 1531

Alfa AF: 0.00198 Hom.: 103

Bravo AF: 0.00699

ESP6500AA AF: 0.0191 AC: 66

ESP6500EA AF: 0.000307 AC: 2

ExAC AF: 0.00185 AC: 224

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (3)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FG syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.32	N
PhyloP100		0.79
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.027
Sift	Benign	0.26	T
Sift4G	Benign	0.15	T
Polyphen		0.0060	B
Vest4		0.17
MVP		0.63
MPC		0.72
ClinPred		0.0020	T
GERP RS		1.4
Varity_R		0.061
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs147354926; hg19: chrX-70357135; COSMIC: COSV107371103;