rs139822988
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_030973.4(MED25):c.956C>A(p.Pro319His) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P319L) has been classified as Uncertain significance.
Frequency
Consequence
NM_030973.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.956C>A | p.Pro319His | missense_variant | 9/18 | ENST00000312865.10 | |
MED25 | NM_001378355.1 | c.956C>A | p.Pro319His | missense_variant | 9/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.956C>A | p.Pro319His | missense_variant | 9/18 | 1 | NM_030973.4 | ||
MED25 | ENST00000538643.5 | c.317C>A | p.Pro106His | missense_variant | 4/13 | 1 | |||
MED25 | ENST00000595185.5 | c.688+794C>A | intron_variant | 1 | |||||
MED25 | ENST00000593767.3 | c.956C>A | p.Pro319His | missense_variant | 9/18 | 3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461602Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727090
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 31, 2022 | The c.956C>A (p.P319H) alteration is located in exon 9 (coding exon 9) of the MED25 gene. This alteration results from a C to A substitution at nucleotide position 956, causing the proline (P) at amino acid position 319 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 569245). This variant has not been reported in the literature in individuals affected with MED25-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 319 of the MED25 protein (p.Pro319His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at