rs767827315

Variant names:

• chrX-71140752-GCAGCAACAGCAGCAA-G
• rs767827315
• NM_005120.3:c.6177_6191delACAGCAACAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_005120.3(MED12):​c.6177_6191delACAGCAACAGCAGCA​(p.Gln2060_Gln2064del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q2059Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.66
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3

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.6177_6191delACAGCAACAGCAGCA	p.Gln2060_Gln2064del	disruptive_inframe_deletion	Exon 42 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.6177_6191delACAGCAACAGCAGCA	p.Gln2060_Gln2064del	disruptive_inframe_deletion	Exon 42 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.6186_6200delACAGCAACAGCAGCA	p.Gln2063_Gln2067del	disruptive_inframe_deletion	Exon 42 of 45	ENSP00000363215.2
	MED12	ENST00000938012.1		c.6219_6233delACAGCAACAGCAGCA	p.Gln2074_Gln2078del	disruptive_inframe_deletion	Exon 42 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 178795 AF XY: 0.00

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: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000456 AC: 5 AN: 1097511 Hom.: 0 AF XY: 0.00000826 AC XY: 3 AN XY: 363023

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841835

Other (OTH) AF: 0.00 AC: 0 AN: 46051

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Blepharophimosis - intellectual disability syndrome, MKB type (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	FG syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767827315; hg19: chrX-70360602;