X-71136507-C-T

Variant names:

• chrX-71136507-C-T
• rs748064846
• NM_005120.3:c.5252C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_005120.3(MED12):​c.5252C>T​(p.Pro1751Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,201,147 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1751Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000024 (0 hom. 11 hem.)
• Consequence: MED12 NM_005120.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.52
• 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: 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26080877).
• BP6: Variant X-71136507-C-T is Benign according to our data. Variant chrX-71136507-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 519898.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000239 (26/1090020) while in subpopulation SAS AF = 0.000094 (5/53219). AF 95% confidence interval is 0.0000369. There are 0 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 11 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.5252C>T	p.Pro1751Leu	missense	Exon 37 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.5252C>T	p.Pro1751Leu	missense	Exon 37 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.5252C>T	p.Pro1751Leu	missense	Exon 37 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.5294C>T	p.Pro1765Leu	missense	Exon 37 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111075 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000250 AC: 4 AN: 160170 AF XY: 0.0000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000145

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 26 AN: 1090020 Hom.: 0 Cov.: 33 AF XY: 0.0000308 AC XY: 11 AN XY: 356976

African (AFR) AF: 0.00 AC: 0 AN: 26204

American (AMR) AF: 0.00 AC: 0 AN: 34120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19271

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29886

South Asian (SAS) AF: 0.0000940 AC: 5 AN: 53219

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40023

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3464

European-Non Finnish (NFE) AF: 0.0000227 AC: 19 AN: 838124

Other (OTH) AF: 0.0000219 AC: 1 AN: 45709

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111127 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33355

African (AFR) AF: 0.00 AC: 0 AN: 30557

American (AMR) AF: 0.00 AC: 0 AN: 10478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5997

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

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52922

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.32
Sift	Benign	0.069	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.27		Loss of glycosylation at P1751 (P = 0.0192)
MVP		0.73
MPC		1.8
ClinPred		0.89	D
GERP RS		4.2
PromoterAI		0.011	Neutral
Varity_R		0.49
gMVP		0.45
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748064846; hg19: chrX-70356357; COSMIC: COSV100377972; COSMIC: COSV100377972;