rs878855132
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_030973.4(MED25):c.1952T>G(p.Leu651Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L651F) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
MED25
NM_030973.4 missense
NM_030973.4 missense
Scores
4
5
5
Clinical Significance
Conservation
PhyloP100: 6.01
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.1952T>G | p.Leu651Arg | missense_variant | 16/18 | ENST00000312865.10 | |
MED25 | NM_001378355.1 | c.1952T>G | p.Leu651Arg | missense_variant | 16/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.1952T>G | p.Leu651Arg | missense_variant | 16/18 | 1 | NM_030973.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000409 AC: 1AN: 244338Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133882
GnomAD3 exomes
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AC:
1
AN:
244338
Hom.:
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AC XY:
1
AN XY:
133882
Gnomad AFR exome
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GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2017 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MED25-related disease. ClinVar contains an entry for this variant (Variation ID: 241614). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 651 of the MED25 protein (p.Leu651Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;.;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Sift4G
Benign
T;T;T;T;T;.
Polyphen
1.0
.;.;D;.;.;.
Vest4
MutPred
0.34
.;.;Gain of solvent accessibility (P = 0.0171);.;.;.;
MVP
MPC
0.64
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at