rs5030619

Variant names:

• chrX-71130097-A-C
• rs5030619
• NM_005120.3:c.3930A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005120.3(MED12):​c.3930A>C​(p.Pro1310Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,206,739 control chromosomes in the GnomAD database, including 36,144 homozygotes. There are 108,959 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (2601 hom., 7027 hem., cov: 24)
  • Exomes 𝑓: 0.29 (33543 hom. 101932 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.08
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-71130097-A-C is Benign according to our data. Variant chrX-71130097-A-C is described in ClinVar as Benign. ClinVar VariationId is 95248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

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.3930A>C	p.Pro1310Pro	synonymous	Exon 28 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.3930A>C	p.Pro1310Pro	synonymous	Exon 28 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.3930A>C	p.Pro1310Pro	synonymous	Exon 28 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.3972A>C	p.Pro1324Pro	synonymous	Exon 28 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 24407 AN: 111958 Hom.: 2603 Cov.: 24

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0922

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.269

GnomAD2 exomes AF: 0.220 AC: 38184 AN: 173323 AF XY: 0.223

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.00143

Gnomad FIN exome AF: 0.262

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.287 AC: 314096 AN: 1094726 Hom.: 33543 Cov.: 34 AF XY: 0.283 AC XY: 101932 AN XY: 360392

African (AFR) AF: 0.0516 AC: 1362 AN: 26377

American (AMR) AF: 0.135 AC: 4700 AN: 34888

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 7825 AN: 19348

East Asian (EAS) AF: 0.000961 AC: 29 AN: 30168

South Asian (SAS) AF: 0.121 AC: 6452 AN: 53541

European-Finnish (FIN) AF: 0.269 AC: 10840 AN: 40292

Middle Eastern (MID) AF: 0.405 AC: 1663 AN: 4107

European-Non Finnish (NFE) AF: 0.319 AC: 268285 AN: 840046

Other (OTH) AF: 0.282 AC: 12940 AN: 45959

GnomAD4 genome AF: 0.218 AC: 24399 AN: 112013 Hom.: 2601 Cov.: 24 AF XY: 0.205 AC XY: 7027 AN XY: 34213

African (AFR) AF: 0.0555 AC: 1717 AN: 30934

American (AMR) AF: 0.192 AC: 2039 AN: 10628

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1073 AN: 2643

East Asian (EAS) AF: 0.00252 AC: 9 AN: 3573

South Asian (SAS) AF: 0.0932 AC: 256 AN: 2746

European-Finnish (FIN) AF: 0.264 AC: 1592 AN: 6024

Middle Eastern (MID) AF: 0.488 AC: 104 AN: 213

European-Non Finnish (NFE) AF: 0.319 AC: 16944 AN: 53063

Other (OTH) AF: 0.267 AC: 407 AN: 1526

Alfa AF: 0.283 Hom.: 16781

Bravo AF: 0.207

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Blepharophimosis - intellectual disability syndrome, MKB type (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	FG syndrome (1)
-	-	1	FG syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	X-linked intellectual disability with marfanoid habitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.69
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5030619; hg19: chrX-70349947; COSMIC: COSV61340557; COSMIC: COSV61340557;