rs764789036

Variant names:

• chrX-71141265-GCAGCAA-G
• rs764789036
• NM_005120.3:c.6315_6320delACAGCA

Your query was ambiguous. Multiple possible variants found:

• chrX-71141265-GCAGCAA-G
• chrX-71141265-GCAGCAA-GCAGCAACAGCAA

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.6315_6320delACAGCA​(p.Gln2106_Gln2107del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,159,273 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 52 hem.)
• Consequence: MED12 NM_005120.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.50

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-71141265-GCAGCAA-G is Benign according to our data. Variant chrX-71141265-GCAGCAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 458830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000202 (22/108870) while in subpopulation NFE AF= 0.000402 (21/52274). AF 95% confidence interval is 0.000268. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.6315_6320delACAGCA	p.Gln2106_Gln2107del	disruptive_inframe_deletion	Exon 43 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6315_6320delACAGCA	p.Gln2106_Gln2107del	disruptive_inframe_deletion	Exon 43 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.000202 AC: 22 AN: 108870 Hom.: 0 Cov.: 23 AF XY: 0.000190 AC XY: 6 AN XY: 31608

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000984

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: 0.000402

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000106 AC: 12 AN: 113583 Hom.: 0 AF XY: 0.0000738 AC XY: 3 AN XY: 40659

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 166 AN: 1050403 Hom.: 0 AF XY: 0.000152 AC XY: 52 AN XY: 341557

Gnomad4 AFR exome AF: 0.0000402

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.000384

GnomAD4 genome AF: 0.000202 AC: 22 AN: 108870 Hom.: 0 Cov.: 23 AF XY: 0.000190 AC XY: 6 AN XY: 31608

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000984

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000402

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MED12: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2024

- -

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: rs764789036; hg19: chrX-70361115;