19-49828539-C-T
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6BP7BS1
The NM_030973.4(MED25):c.396C>T(p.Arg132Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,613,120 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )
Consequence
MED25
NM_030973.4 synonymous
NM_030973.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.392
Genes affected
MED25 (HGNC:28845): (mediator complex subunit 25) This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2. [provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
Variant 19-49828539-C-T is Benign according to our data. Variant chr19-49828539-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287305.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
BP7
Synonymous conserved (PhyloP=-0.392 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00116 (177/152308) while in subpopulation AFR AF= 0.00356 (148/41558). AF 95% confidence interval is 0.00309. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MED25 | NM_030973.4 | c.396C>T | p.Arg132Arg | synonymous_variant | 4/18 | ENST00000312865.10 | NP_112235.2 | |
| MED25 | NM_001378355.1 | c.396C>T | p.Arg132Arg | synonymous_variant | 4/18 | NP_001365284.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MED25 | ENST00000312865.10 | c.396C>T | p.Arg132Arg | synonymous_variant | 4/18 | 1 | NM_030973.4 | ENSP00000326767.5 | ||
| MED25 | ENST00000595185.5 | c.396C>T | p.Arg132Arg | synonymous_variant | 4/7 | 1 | ENSP00000470027.1 | |||
| MED25 | ENST00000538643.5 | c.181-1972C>T | intron_variant | 1 | ENSP00000437496.1 | |||||
| MED25 | ENST00000593767.3 | c.396C>T | p.Arg132Arg | synonymous_variant | 4/18 | 3 | ENSP00000470692.3 |
Frequencies
GnomAD3 genomes 0.00116 AC: 177AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000394 AC: 99AN: 251316Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135896
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GnomAD4 exome AF: 0.000174 AC: 254AN: 1460812Hom.: 0 Cov.: 31 AF XY: 0.000153 AC XY: 111AN XY: 726800
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GnomAD4 genome 0.00116 AC: 177AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | MED25: BP4, BP7 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 13, 2016 | - - |
Charcot-Marie-Tooth disease Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 2 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | - - |
MED25-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 25, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
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DANN
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RBP_binding_hub_radar
RBP_regulation_power_radar
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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