rs727503869

chrX-71141271-ACAGCAACAGCAGCAG-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_005120.3(MED12):c.6321_6335del(p.Gln2111_Gln2115del) variant causes a 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q2104Q) 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 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.01

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 166877.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=1}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.6321_6335del	p.Gln2111_Gln2115del	inframe_deletion	43/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.6321_6335del	p.Gln2111_Gln2115del	inframe_deletion	43/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 51 AN: 110952 Hom.: 0 Cov.: 23 AF XY: 0.000389 AC XY: 13 AN XY: 33380

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

GnomAD3 exomes AF: 0.000432 AC: 49 AN: 113535 Hom.: 0 AF XY: 0.000296 AC XY: 12 AN XY: 40577

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 SAS 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

Gnomad4 AFR exome AF: 0.0000808

Gnomad4 AMR exome AF: 0.0000717

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000531

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000680

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

Gnomad4 AFR AF: 0.000263

Gnomad4 AMR AF: 0.000192

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000166

Gnomad4 NFE AF: 0.000758

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000434 Hom.: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

FG syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This variant, c.6321_6335del, results in the deletion of 5 amino acid(s) of the MED12 protein (p.Gln2111_Gln2115del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MED12-related conditions. ClinVar contains an entry for this variant (Variation ID: 166877). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 18, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2016

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

MED12-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503869; hg19: chrX-70361121;