rs772462354

chrX-71136905-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005120.3(MED12):c.5427C>T(p.Ser1809=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000902 in 1,208,815 control chromosomes in the GnomAD database, including 1 homozygotes. There are 59 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 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000097 (1 hom. 58 hem.)
• Consequence: MED12 NM_005120.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.98

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant X-71136905-C-T is Benign according to our data. Variant chrX-71136905-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415263.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000966 (106/1097789) while in subpopulation SAS AF= 0.00127 (69/54140). AF 95% confidence interval is 0.00103. There are 1 homozygotes in gnomad4_exome. There are 58 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MED12	NM_005120.3	c.5427C>T	p.Ser1809=	synonymous_variant	38/45	ENST00000374080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MED12	ENST00000374080.8	c.5427C>T	p.Ser1809=	synonymous_variant	38/45	1	NM_005120.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111026 Hom.: 0 Cov.: 22 AF XY: 0.0000301 AC XY: 1 AN XY: 33216

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000957

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000145 AC: 26 AN: 179930 Hom.: 0 AF XY: 0.000242 AC XY: 16 AN XY: 66118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000739

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000497

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000966 AC: 106 AN: 1097789 Hom.: 1 Cov.: 33 AF XY: 0.000160 AC XY: 58 AN XY: 363217

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000392

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111026 Hom.: 0 Cov.: 22 AF XY: 0.0000301 AC XY: 1 AN XY: 33216

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000957

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000283

Gnomad4 SAS AF: 0.000381

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

FG syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.30
Dann	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs772462354; hg19: chrX-70356755; COSMIC: COSV61345370;