X-71125743-C-T

Variant names:

• chrX-71125743-C-T
• rs2075790
• NM_005120.3:c.2422+30C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005120.3(MED12):​c.2422+30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,059,878 control chromosomes in the GnomAD database, including 6,235 homozygotes. There are 46,414 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (726 hom., 3121 hem., cov: 18)
  • Exomes 𝑓: 0.14 (5509 hom. 43293 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.236
• Publications: 5 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=-0.74).
• BP6: Variant X-71125743-C-T is Benign according to our data. Variant chrX-71125743-C-T is described in ClinVar as Benign. ClinVar VariationId is 259634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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.2422+30C>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.2422+30C>T		intron	N/A	ENSP00000363193.3
	MED12	ENST00000374102.6	TSL:1	c.2422+30C>T		intron	N/A	ENSP00000363215.2
	MED12	ENST00000690145.1		c.2422+30C>T		intron	N/A	ENSP00000508818.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 13256 AN: 101861 Hom.: 722 Cov.: 18

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0233

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.133 AC: 23533 AN: 176424 AF XY: 0.143

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0938

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.136 AC: 129921 AN: 957961 Hom.: 5509 Cov.: 28 AF XY: 0.159 AC XY: 43293 AN XY: 272939

African (AFR) AF: 0.180 AC: 4222 AN: 23431

American (AMR) AF: 0.102 AC: 3472 AN: 33996

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 1791 AN: 17522

East Asian (EAS) AF: 0.130 AC: 3481 AN: 26869

South Asian (SAS) AF: 0.235 AC: 12123 AN: 51493

European-Finnish (FIN) AF: 0.132 AC: 4734 AN: 35933

Middle Eastern (MID) AF: 0.128 AC: 484 AN: 3782

European-Non Finnish (NFE) AF: 0.130 AC: 93842 AN: 724467

Other (OTH) AF: 0.143 AC: 5772 AN: 40468

GnomAD4 genome AF: 0.130 AC: 13270 AN: 101917 Hom.: 726 Cov.: 18 AF XY: 0.119 AC XY: 3121 AN XY: 26163

African (AFR) AF: 0.164 AC: 4557 AN: 27834

American (AMR) AF: 0.103 AC: 972 AN: 9413

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 236 AN: 2543

East Asian (EAS) AF: 0.132 AC: 396 AN: 3005

South Asian (SAS) AF: 0.233 AC: 460 AN: 1977

European-Finnish (FIN) AF: 0.112 AC: 531 AN: 4732

Middle Eastern (MID) AF: 0.108 AC: 22 AN: 204

European-Non Finnish (NFE) AF: 0.118 AC: 5907 AN: 50166

Other (OTH) AF: 0.124 AC: 174 AN: 1398

Alfa AF: 0.125 Hom.: 1360

Bravo AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

X-linked intellectual disability with marfanoid habitus Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FG syndrome 1 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Blepharophimosis - intellectual disability syndrome, MKB type Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.64
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2075790; hg19: chrX-70345593; COSMIC: COSV61330752; COSMIC: COSV61330752;