rs750162341
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_005120.3(MED12):c.4253+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,208,424 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 22)
Exomes 𝑓: 0.000064 ( 0 hom. 23 hem. )
Consequence
MED12
NM_005120.3 splice_donor_region, intron
NM_005120.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001777
2
Clinical Significance
Conservation
PhyloP100: 2.80
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 -8 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BS2
?
High Hemizygotes in GnomAd4 at 2 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED12 | NM_005120.3 | c.4253+4G>A | splice_donor_region_variant, intron_variant | ENST00000374080.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED12 | ENST00000374080.8 | c.4253+4G>A | splice_donor_region_variant, intron_variant | 1 | NM_005120.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000445 AC: 5AN: 112278Hom.: 0 Cov.: 22 AF XY: 0.0000581 AC XY: 2AN XY: 34440
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GnomAD3 exomes AF: 0.0000112 AC: 2AN: 179108Hom.: 0 AF XY: 0.0000154 AC XY: 1AN XY: 65078
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GnomAD4 exome AF: 0.0000639 AC: 70AN: 1096146Hom.: 0 Cov.: 31 AF XY: 0.0000636 AC XY: 23AN XY: 361572
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2024 | The c.4253+4G>A intronic variant results from a G to A substitution 4 nucleotides after coding exon 30 in the MED12 gene. Based on data from gnomAD, the A allele has an overall frequency of 0.0015% (3/201088) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0022% (2/90975) of European (non-Finnish) alleles. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 18, 2020 | ACMG classification criteria: PM2, BP4 - |
FG syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change falls in intron 30 of the MED12 gene. It does not directly change the encoded amino acid sequence of the MED12 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs750162341, gnomAD 0.002%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MED12-related conditions. ClinVar contains an entry for this variant (Variation ID: 264566). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at