rs202125318

Variant names:

• chrX-71119862-G-A
• rs202125318
• NM_005120.3:c.381G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-71119862-G-A
• chrX-71119862-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005120.3(MED12):​c.381G>A​(p.Thr127Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,209,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 72 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., 12 hem., cov: 22)
  • Exomes 𝑓: 0.00019 (0 hom. 60 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.388
• Publications: 1 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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP6: Variant X-71119862-G-A is Benign according to our data. Variant chrX-71119862-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196405.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000403 (45/111712) while in subpopulation AFR AF = 0.000943 (29/30758). AF 95% confidence interval is 0.000674. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 12 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.381G>A	p.Thr127Thr	synonymous	Exon 3 of 45	NP_005111.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.381G>A	p.Thr127Thr	synonymous	Exon 3 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.381G>A	p.Thr127Thr	synonymous	Exon 3 of 45	ENSP00000363215.2
	MED12	ENST00000938012.1		c.381G>A	p.Thr127Thr	synonymous	Exon 3 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 44 AN: 111656 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

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: 0.000264

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 33 AN: 180586 AF XY: 0.000165

Gnomad AFR exome AF: 0.000488

Gnomad AMR exome AF: 0.0000733

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000191 AC: 210 AN: 1097813 Hom.: 0 Cov.: 32 AF XY: 0.000165 AC XY: 60 AN XY: 363171

African (AFR) AF: 0.000720 AC: 19 AN: 26392

American (AMR) AF: 0.000142 AC: 5 AN: 35170

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.000166 AC: 9 AN: 54072

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40511

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4119

European-Non Finnish (NFE) AF: 0.000192 AC: 162 AN: 841895

Other (OTH) AF: 0.000239 AC: 11 AN: 46076

GnomAD4 genome AF: 0.000403 AC: 45 AN: 111712 Hom.: 0 Cov.: 22 AF XY: 0.000354 AC XY: 12 AN XY: 33914

African (AFR) AF: 0.000943 AC: 29 AN: 30758

American (AMR) AF: 0.000189 AC: 2 AN: 10575

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6029

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

European-Non Finnish (NFE) AF: 0.000264 AC: 14 AN: 53073

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.000434 Hom.: 4

Bravo AF: 0.000355

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FG syndrome (1)
-	-	1	MED12-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.9
DANN	Benign	0.65
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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: rs202125318; hg19: chrX-70339712; COSMIC: COSV61358732;