rs140083803

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• blepharophimosis - intellectual disability syndrome, MKB type

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	NM_005120.3	MANE Select	c.6045-24C>T		intron	N/A	NP_005111.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MED12	ENST00000374080.8	TSL:1 MANE Select	c.6045-24C>T		intron	N/A	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.6054-24C>T		intron	N/A	ENSP00000363215.2
	MED12	ENST00000690523.1		n.2131C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1278 AN: 110661 Hom.: 12 Cov.: 22

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

GnomAD2 exomes AF: 0.00987 AC: 1775 AN: 179847 AF XY: 0.00967

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 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

African (AFR) AF: 0.00182 AC: 48 AN: 26399

American (AMR) AF: 0.00682 AC: 240 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 23 AN: 19383

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30205

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54145

European-Finnish (FIN) AF: 0.0118 AC: 479 AN: 40492

Middle Eastern (MID) AF: 0.00387 AC: 16 AN: 4135

European-Non Finnish (NFE) AF: 0.0175 AC: 14728 AN: 841962

Other (OTH) AF: 0.0115 AC: 529 AN: 46087

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

African (AFR) AF: 0.00213 AC: 65 AN: 30447

American (AMR) AF: 0.0128 AC: 132 AN: 10335

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2641

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3525

South Asian (SAS) AF: 0.000767 AC: 2 AN: 2609

European-Finnish (FIN) AF: 0.0107 AC: 63 AN: 5871

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.0170 AC: 898 AN: 52897

Other (OTH) AF: 0.0127 AC: 19 AN: 1501

Alfa AF: 0.0143 Hom.: 110

Bravo AF: 0.0120

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		-0.042
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs140083803; hg19: chrX-70360461;