rs727503869

Variant names:

• chrX-71141271-ACAGCAACAGCAGCAG-A
• rs727503869
• NM_005120.3:c.6321_6335delGCAGCAGCAACAGCA

Your query was ambiguous. Multiple possible variants found:

• chrX-71141271-ACAGCAACAGCAGCAG-A
• chrX-71141271-ACAGCAACAGCAGCAG-ACAGCAACAGCAGCAGCAGCAACAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_005120.3(MED12):​c.6321_6335delGCAGCAGCAACAGCA​(p.Gln2108_Gln2112del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000819 in 1,157,316 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 258 hemizygotes in GnomAD. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q2107Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00086 (0 hom. 245 hem.)
• Consequence: MED12 NM_005120.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.01
• 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: 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005120.3
• BP6: Variant X-71141271-ACAGCAACAGCAGCAG-A is Benign according to our data. Variant chrX-71141271-ACAGCAACAGCAGCAG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166877.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00046 (51/110952) while in subpopulation NFE AF = 0.000758 (40/52791). AF 95% confidence interval is 0.000572. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 13 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.6321_6335delGCAGCAGCAACAGCA	p.Gln2108_Gln2112del	disruptive_inframe_deletion	Exon 43 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.6321_6335delGCAGCAGCAACAGCA	p.Gln2108_Gln2112del	disruptive_inframe_deletion	Exon 43 of 45	ENSP00000363193.3	Q93074-1
	MED12	ENST00000374102.6	TSL:1	c.6330_6344delGCAGCAGCAACAGCA	p.Gln2111_Gln2115del	disruptive_inframe_deletion	Exon 43 of 45	ENSP00000363215.2	Q93074-2
	MED12	ENST00000938012.1		c.6363_6377delGCAGCAGCAACAGCA	p.Gln2122_Gln2126del	disruptive_inframe_deletion	Exon 43 of 45	ENSP00000608071.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 51 AN: 110952 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000758

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000432 AC: 49 AN: 113535 AF XY: 0.000296

Gnomad AFR exome AF: 0.000306

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000711

Gnomad NFE exome AF: 0.000861

Gnomad OTH exome AF: 0.000306

GnomAD4 exome AF: 0.000857 AC: 897 AN: 1046364 Hom.: 0 AF XY: 0.000724 AC XY: 245 AN XY: 338476

African (AFR) AF: 0.0000808 AC: 2 AN: 24754

American (AMR) AF: 0.0000717 AC: 2 AN: 27894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18579

East Asian (EAS) AF: 0.00 AC: 0 AN: 27093

South Asian (SAS) AF: 0.00 AC: 0 AN: 49724

European-Finnish (FIN) AF: 0.000531 AC: 20 AN: 37640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00104 AC: 843 AN: 812552

Other (OTH) AF: 0.000680 AC: 30 AN: 44091

GnomAD4 genome AF: 0.000460 AC: 51 AN: 110952 Hom.: 0 Cov.: 23 AF XY: 0.000389 AC XY: 13 AN XY: 33380

African (AFR) AF: 0.000263 AC: 8 AN: 30468

American (AMR) AF: 0.000192 AC: 2 AN: 10429

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2626

East Asian (EAS) AF: 0.00 AC: 0 AN: 3553

South Asian (SAS) AF: 0.00 AC: 0 AN: 2658

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.000758 AC: 40 AN: 52791

Other (OTH) AF: 0.00 AC: 0 AN: 1487

Alfa AF: 0.000434 Hom.: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	FG syndrome (1)
-	-	1	MED12-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=183/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs727503869; hg19: chrX-70361121;