rs140083803

Variant names:

• chrX-71140611-C-T
• rs140083803
• NM_005120.3:c.6045-24C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005120.3(MED12):​c.6045-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,208,727 control chromosomes in the GnomAD database, including 97 homozygotes. There are 5,416 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., 362 hem., cov: 22)
  • Exomes 𝑓: 0.015 (85 hom. 5054 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0420

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-71140611-C-T is Benign according to our data. Variant chrX-71140611-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259640.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 = 0.0115 (1278/110715) while in subpopulation NFE AF= 0.017 (898/52897). AF 95% confidence interval is 0.0161. There are 12 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.6045-24C>T		intron_variant	Intron 41 of 44	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.6045-24C>T		intron_variant	Intron 41 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1278 AN: 110661 Hom.: 12 Cov.: 22 AF XY: 0.0110 AC XY: 362 AN XY: 32867

Gnomad AFR AF: 0.00214

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.000764

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0128

GnomAD3 exomes AF: 0.00987 AC: 1775 AN: 179847 Hom.: 2 AF XY: 0.00967 AC XY: 648 AN XY: 67001

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00603

Gnomad ASJ exome AF: 0.000937

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0146 AC: 16081 AN: 1098012 Hom.: 85 Cov.: 32 AF XY: 0.0139 AC XY: 5054 AN XY: 363384

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00682

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000296

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0115 AC: 1278 AN: 110715 Hom.: 12 Cov.: 22 AF XY: 0.0110 AC XY: 362 AN XY: 32931

Gnomad4 AFR AF: 0.00213

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.000284

Gnomad4 SAS AF: 0.000767

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0127

Alfa AF: 0.0143 Hom.: 110

Bravo AF: 0.0120

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140083803; hg19: chrX-70360461;