rs10521349

Variant names:

• chrX-71132567-T-C
• rs10521349
• NM_005120.3:c.4415+29T>C

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.4415+29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,162,723 control chromosomes in the GnomAD database, including 35,570 homozygotes. There are 105,229 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (2670 hom., 7057 hem., cov: 22)
  • Exomes 𝑓: 0.29 (32900 hom. 98172 hem.)
• Consequence: MED12 NM_005120.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.381
• Publications: 6 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=-0.85).
• BP6: Variant X-71132567-T-C is Benign according to our data. Variant chrX-71132567-T-C is described in ClinVar as Benign. ClinVar VariationId is 259637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.4415+29T>C		intron_variant	Intron 31 of 44	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.4415+29T>C		intron_variant	Intron 31 of 44	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.228 AC: 25139 AN: 110150 Hom.: 2672 Cov.: 22

Gnomad AFR AF: 0.0870

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.00254

Gnomad SAS AF: 0.0914

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.227 AC: 26337 AN: 116232 AF XY: 0.223

Gnomad AFR exome AF: 0.0809

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.00169

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.290

GnomAD4 exome AF: 0.291 AC: 305906 AN: 1052520 Hom.: 32900 Cov.: 31 AF XY: 0.287 AC XY: 98172 AN XY: 342402

African (AFR) AF: 0.0836 AC: 2086 AN: 24962

American (AMR) AF: 0.144 AC: 4036 AN: 28011

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 7468 AN: 18628

East Asian (EAS) AF: 0.000991 AC: 27 AN: 27256

South Asian (SAS) AF: 0.122 AC: 6090 AN: 49904

European-Finnish (FIN) AF: 0.270 AC: 10194 AN: 37798

Middle Eastern (MID) AF: 0.409 AC: 1599 AN: 3906

European-Non Finnish (NFE) AF: 0.320 AC: 261781 AN: 817705

Other (OTH) AF: 0.285 AC: 12625 AN: 44350

GnomAD4 genome AF: 0.228 AC: 25139 AN: 110203 Hom.: 2670 Cov.: 22 AF XY: 0.217 AC XY: 7057 AN XY: 32555

African (AFR) AF: 0.0870 AC: 2643 AN: 30364

American (AMR) AF: 0.199 AC: 2064 AN: 10353

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1048 AN: 2614

East Asian (EAS) AF: 0.00255 AC: 9 AN: 3527

South Asian (SAS) AF: 0.0928 AC: 240 AN: 2585

European-Finnish (FIN) AF: 0.264 AC: 1524 AN: 5764

Middle Eastern (MID) AF: 0.498 AC: 105 AN: 211

European-Non Finnish (NFE) AF: 0.320 AC: 16832 AN: 52619

Other (OTH) AF: 0.275 AC: 414 AN: 1503

Alfa AF: 0.285 Hom.: 17194

Bravo AF: 0.218

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: 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: 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.93
DANN	Benign	0.51
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10521349; hg19: chrX-70352417; COSMIC: COSV61340572; COSMIC: COSV61340572;