X-71118727-G-T

Variant names:

• chrX-71118727-G-T
• rs373552360
• NM_005120.3:c.-28G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_005120.3(MED12):​c.-28G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000925 in 1,188,876 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 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 0.000055 (0 hom., 3 hem., cov: 20)
  • Exomes 𝑓: 0.000096 (0 hom. 36 hem.)
• Consequence: MED12 NM_005120.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50
• Publications: 0 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant X-71118727-G-T is Benign according to our data. Variant chrX-71118727-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 507960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000545 (6/110088) while in subpopulation NFE AF = 0.000095 (5/52632). AF 95% confidence interval is 0.0000372. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MED12	NM_005120.3	c.-28G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 45	ENST00000374080.8	NP_005111.2
MED12	NM_005120.3	c.-28G>T		5_prime_UTR_variant	Exon 1 of 45	ENST00000374080.8	NP_005111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MED12	ENST00000374080.8	c.-28G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 45	1	NM_005120.3	ENSP00000363193.3
MED12	ENST00000374080.8	c.-28G>T		5_prime_UTR_variant	Exon 1 of 45	1	NM_005120.3	ENSP00000363193.3

Frequencies

GnomAD3 genomes AF: 0.0000545 AC: 6 AN: 110088 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000950

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000462 AC: 7 AN: 151614 AF XY: 0.0000830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000964 AC: 104 AN: 1078788 Hom.: 0 Cov.: 29 AF XY: 0.000103 AC XY: 36 AN XY: 348328

African (AFR) AF: 0.00 AC: 0 AN: 25890

American (AMR) AF: 0.00 AC: 0 AN: 34002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19133

East Asian (EAS) AF: 0.00 AC: 0 AN: 29420

South Asian (SAS) AF: 0.00 AC: 0 AN: 52286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39447

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3872

European-Non Finnish (NFE) AF: 0.000125 AC: 104 AN: 829412

Other (OTH) AF: 0.00 AC: 0 AN: 45326

GnomAD4 genome AF: 0.0000545 AC: 6 AN: 110088 Hom.: 0 Cov.: 20 AF XY: 0.0000928 AC XY: 3 AN XY: 32326

African (AFR) AF: 0.0000331 AC: 1 AN: 30207

American (AMR) AF: 0.00 AC: 0 AN: 10366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2622

East Asian (EAS) AF: 0.00 AC: 0 AN: 3501

South Asian (SAS) AF: 0.00 AC: 0 AN: 2542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5833

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000950 AC: 5 AN: 52632

Other (OTH) AF: 0.00 AC: 0 AN: 1473

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 17, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		1.5
PromoterAI		0.028	Neutral
Mutation Taster		=300/0	polymorphism

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: rs373552360; hg19: chrX-70338577; COSMIC: COSV61334876;