chr19-49818343-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_030973.4(MED25):c.2T>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
MED25
NM_030973.4 start_lost
NM_030973.4 start_lost
Scores
4
5
3
Clinical Significance
Conservation
PhyloP100: 4.06
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 Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-49818343-T-G is Pathogenic according to our data. Variant chr19-49818343-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3063666.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.2T>G | p.Met1? | start_lost | 1/18 | ENST00000312865.10 | |
MED25 | NM_001378355.1 | c.2T>G | p.Met1? | start_lost | 1/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.2T>G | p.Met1? | start_lost | 1/18 | 1 | NM_030973.4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 24, 2024 | Variant summary: MED25 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. A rare, homozygous missense variant p.Tyr39Cys, upstream of the next downstream in-frame Met104, has been reported in at-least 4 families with Basel-Vanagait-Smirin-Yosef syndrome, and segregated with disease; subsequent functional study found p.Tyr39Cys impaired MED25 interaction with the Mediator complex in mammalian cells (PMID: 25792360, ClinVar ID 203445). The current variant was absent in 203948 control chromosomes. To our knowledge, no occurrence of c.2T>G in individuals affected with Congenital Cataract-Microcephaly Flammeus Simplex-Severe Intellectual Disability Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
0.93
.;.;.;.;P;.;.;.;.
Vest4
MutPred
Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);Gain of methylation at M1 (P = 0.0173);
MVP
ClinPred
D
GERP RS
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
Publications
No publications associated with this variant yet.