chr19-49835757-CAG-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_030973.4(MED25):c.1778_1779delAG(p.Gln593ArgfsTer167) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_030973.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.1778_1779delAG | p.Gln593ArgfsTer167 | frameshift_variant | Exon 16 of 18 | ENST00000312865.10 | NP_112235.2 | |
MED25 | NM_001378355.1 | c.1778_1779delAG | p.Gln593ArgfsTer174 | frameshift_variant | Exon 16 of 18 | NP_001365284.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000126 AC: 3AN: 238374Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130612
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1458500Hom.: 0 AF XY: 0.0000165 AC XY: 12AN XY: 725520
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74464
ClinVar
Submissions by phenotype
Sensory neuropathy;C0240991:Sensory ataxia;C0856863:Broad-based gait;C1843859:Sensory ataxic neuropathy;C1858120:Generalized hypotonia;C2315100:Failure to thrive;C4021585:Impaired distal proprioception;C5574742:Decreased body weight Uncertain:1
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Charcot-Marie-Tooth disease type 2 Uncertain:1
The current clinical and genetic evidence is not sufficient to establish whether this type of variant in MED25 causes disease. Therefore, this variant has been classified as a Variant of Uncertain Significance. This variant is present in population databases at a very low frequency (rs763039409, ExAC 0.01%) but has not been reported in the literature in individuals with a MED25-related disease. This sequence change deletes 2 nucleotide from exon 16 of the MED25 mRNA (c.1778_1779delAG), causing a frameshift at codon 593. This creates a new reading frame which does not encounter a premature termination codon, but is expected to result in disrupted protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at