rs778775959
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_030973.4(MED25):c.295G>A(p.Asp99Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,594,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000071 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
MED25
NM_030973.4 missense
NM_030973.4 missense
Scores
3
6
5
Clinical Significance
Conservation
PhyloP100: 7.02
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 4 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_030973.4
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.295G>A | p.Asp99Asn | missense_variant | 3/18 | ENST00000312865.10 | |
MED25 | NM_001378355.1 | c.295G>A | p.Asp99Asn | missense_variant | 3/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.295G>A | p.Asp99Asn | missense_variant | 3/18 | 1 | NM_030973.4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000706 AC: 1AN: 141680Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251340Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1453136Hom.: 0 Cov.: 33 AF XY: 0.00000830 AC XY: 6AN XY: 722858
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GnomAD4 genome ? AF: 0.00000706 AC: 1AN: 141680Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 68884
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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 | Jul 21, 2021 | 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MED25-related disease. This variant is present in population databases (rs778775959, ExAC 0.006%). This sequence change replaces aspartic acid with asparagine at codon 99 of the MED25 protein (p.Asp99Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D;D;D
Polyphen
1.0
.;.;D;.;.
Vest4
MutPred
Gain of ubiquitination at K102 (P = 0.1047);Gain of ubiquitination at K102 (P = 0.1047);Gain of ubiquitination at K102 (P = 0.1047);Gain of ubiquitination at K102 (P = 0.1047);Gain of ubiquitination at K102 (P = 0.1047);
MVP
MPC
1.2
ClinPred
D
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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