chrX-71140797-ACAG-A

Variant names:

• chrX-71140797-ACAG-A
• rs757160341
• NM_005120.3:c.6226_6228delCAG

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_005120.3(MED12):​c.6226_6228delCAG​(p.Gln2076del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000108 in 1,070,004 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00011 (0 hom. 8 hem.)
  • Failed GnomAD Quality Control
• Consequence: MED12 NM_005120.3 conservative_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.36
• Publications: 4 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71140797-ACAG-A is Benign according to our data. Variant chrX-71140797-ACAG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 415265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 8 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.6226_6228delCAG	p.Gln2076del	conservative_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.6226_6228delCAG	p.Gln2076del	conservative_inframe_deletion	Exon 42 of 45	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.6235_6237delCAG	p.Gln2079del	conservative_inframe_deletion	Exon 42 of 45	ENSP00000363215.2
	MED12	ENST00000938012.1		c.6268_6270delCAG	p.Gln2090del	conservative_inframe_deletion	Exon 42 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.0000182 AC: 2 AN: 109877 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000974

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: 0.0000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000261 AC: 44 AN: 168423 AF XY: 0.0000168

Gnomad AFR exome AF: 0.000171

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000108 AC: 116 AN: 1070004 Hom.: 0 AF XY: 0.0000230 AC XY: 8 AN XY: 347250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25787

American (AMR) AF: 0.0000578 AC: 2 AN: 34619

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18854

East Asian (EAS) AF: 0.00 AC: 0 AN: 29495

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52400

European-Finnish (FIN) AF: 0.00110 AC: 42 AN: 38348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 0.0000840 AC: 69 AN: 821551

Other (OTH) AF: 0.0000445 AC: 2 AN: 44898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000182 AC: 2 AN: 109877 Hom.: 0 Cov.: 22 AF XY: 0.0000616 AC XY: 2 AN XY: 32481

African (AFR) AF: 0.00 AC: 0 AN: 30216

American (AMR) AF: 0.0000974 AC: 1 AN: 10272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2585

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 225

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52452

Other (OTH) AF: 0.00 AC: 0 AN: 1465

Alfa AF: 0.00365 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cholestasis-pigmentary retinopathy-cleft palate syndrome;C0796022:X-linked intellectual disability with marfanoid habitus;C3698541:Blepharophimosis - intellectual disability syndrome, MKB type;C5399762:FG syndrome 1 (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		4.4
Mutation Taster		=65/35	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: rs757160341; hg19: chrX-70360647; COSMIC: COSV61351723; COSMIC: COSV61351723;