chr6-131589544-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBS1_Supporting
The NM_004830.4(MED23):āc.3860A>Gā(p.His1287Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00039 ( 0 hom., cov: 32)
Exomes š: 0.00056 ( 0 hom. )
Consequence
MED23
NM_004830.4 missense
NM_004830.4 missense
Scores
1
6
10
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
MED23 (HGNC:2372): (mediator complex subunit 23) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, MED23
BP4
Computational evidence support a benign effect (MetaRNN=0.09958169).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000387 (59/152294) while in subpopulation NFE AF= 0.000764 (52/68022). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED23 | NM_004830.4 | c.3860A>G | p.His1287Arg | missense_variant | 28/29 | ENST00000368068.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED23 | ENST00000368068.8 | c.3860A>G | p.His1287Arg | missense_variant | 28/29 | 1 | NM_004830.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000426 AC: 107AN: 251206Hom.: 0 AF XY: 0.000383 AC XY: 52AN XY: 135770
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GnomAD4 exome AF: 0.000560 AC: 818AN: 1461584Hom.: 0 Cov.: 31 AF XY: 0.000568 AC XY: 413AN XY: 727124
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GnomAD4 genome AF: 0.000387 AC: 59AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 23, 2014 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2021 | The c.3878A>G (p.H1293R) alteration is located in exon 29 (coding exon 29) of the MED23 gene. This alteration results from a A to G substitution at nucleotide position 3878, causing the histidine (H) at amino acid position 1293 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;.;.
Vest4
MVP
MPC
1.3
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at