chrX-71132917-C-T

Variant names:

• chrX-71132917-C-T
• rs531754497
• NM_005120.3:c.4488C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_005120.3(MED12):​c.4488C>T​(p.Arg1496Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000666 in 1,186,268 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 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). Synonymous variant affecting the same amino acid position (i.e. R1496R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 4 hem., cov: 21)
  • Exomes 𝑓: 0.000060 (0 hom. 24 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.284
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-71132917-C-T is Benign according to our data. Variant chrX-71132917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211476.
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000127 (14/110394) while in subpopulation EAS AF = 0.00142 (5/3532). AF 95% confidence interval is 0.000557. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 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.4488C>T	p.Arg1496Arg	synonymous	Exon 32 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.4488C>T	p.Arg1496Arg	synonymous	Exon 32 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.4488C>T	p.Arg1496Arg	synonymous	Exon 32 of 45	ENSP00000363215.2
	MED12	ENST00000938012.1		c.4530C>T	p.Arg1510Arg	synonymous	Exon 32 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 14 AN: 110341 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000992

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000976

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000945

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000180 AC: 26 AN: 144281 AF XY: 0.000248

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000129

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000164

Gnomad OTH exome AF: 0.000265

GnomAD4 exome AF: 0.0000604 AC: 65 AN: 1075874 Hom.: 0 Cov.: 31 AF XY: 0.0000687 AC XY: 24 AN XY: 349324

African (AFR) AF: 0.0000383 AC: 1 AN: 26092

American (AMR) AF: 0.000157 AC: 5 AN: 31920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18923

East Asian (EAS) AF: 0.00139 AC: 41 AN: 29519

South Asian (SAS) AF: 0.00 AC: 0 AN: 51366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3831

European-Non Finnish (NFE) AF: 0.0000121 AC: 10 AN: 829871

Other (OTH) AF: 0.000177 AC: 8 AN: 45256

GnomAD4 genome AF: 0.000127 AC: 14 AN: 110394 Hom.: 0 Cov.: 21 AF XY: 0.000123 AC XY: 4 AN XY: 32622

African (AFR) AF: 0.0000989 AC: 3 AN: 30326

American (AMR) AF: 0.0000975 AC: 1 AN: 10258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00142 AC: 5 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2565

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5807

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

European-Non Finnish (NFE) AF: 0.0000946 AC: 5 AN: 52879

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000208

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	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	-0.43
CADD	Benign	0.39
DANN	Benign	0.71
PhyloP100		-0.28
Mutation Taster		=94/6	polymorphism

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: rs531754497; hg19: chrX-70352767;