X-71118829-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_005120.3(MED12):​c.75C>T​(p.Tyr25Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,094 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 20)
Exomes 𝑓: 0.0000055 ( 0 hom. 2 hem. )

Consequence

MED12
NM_005120.3 synonymous

Scores

1
1

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.41
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
Variant X-71118829-C-T is Benign according to our data. Variant chrX-71118829-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3711530.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=1.41 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000547 (6/1097094) while in subpopulation SAS AF= 0.000074 (4/54036). AF 95% confidence interval is 0.0000253. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MED12NM_005120.3 linkc.75C>T p.Tyr25Tyr synonymous_variant Exon 1 of 45 ENST00000374080.8 NP_005111.2 Q93074-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MED12ENST00000374080.8 linkc.75C>T p.Tyr25Tyr synonymous_variant Exon 1 of 45 1 NM_005120.3 ENSP00000363193.3 Q93074-1

Frequencies

GnomAD3 genomes
Cov.:
20
GnomAD4 exome
AF:
0.00000547
AC:
6
AN:
1097094
Hom.:
0
Cov.:
30
AF XY:
0.00000552
AC XY:
2
AN XY:
362574
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000740
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
20

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

FG syndrome Benign:1
Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.42
CADD
Benign
10
DANN
Uncertain
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70338679; API