rs757160341

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-71140797-ACAG-A
• chrX-71140797-ACAG-ACAGCAG
• chrX-71140797-ACAG-ACAGCAGCAG
• chrX-71140797-ACAG-ACAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 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

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 -17 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 id is 415265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000108 (116/1070004) while in subpopulation NFE AF= 0.000084 (69/821551). AF 95% confidence interval is 0.0000675. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.6226_6228delCAG	p.Gln2076del	conservative_inframe_deletion	Exon 42 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6226_6228delCAG	p.Gln2076del	conservative_inframe_deletion	Exon 42 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 109877 Hom.: 0 Cov.: 22 AF XY: 0.0000616 AC XY: 2 AN XY: 32481 FAILED QC

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

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000578

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000191

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.0000840

Gnomad4 OTH exome AF: 0.0000445

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000974

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00365 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 Benign:1

Dec 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 16, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FG syndrome Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs757160341; hg19: chrX-70360647;