chr19-49828983-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_030973.4(MED25):c.418C>T(p.Arg140Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_030973.4 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.418C>T | p.Arg140Trp | missense_variant | 5/18 | ENST00000312865.10 | |
MED25 | NM_001378355.1 | c.418C>T | p.Arg140Trp | missense_variant | 5/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.418C>T | p.Arg140Trp | missense_variant | 5/18 | 1 | NM_030973.4 | ||
MED25 | ENST00000595185.5 | c.418C>T | p.Arg140Trp | missense_variant | 5/7 | 1 | |||
MED25 | ENST00000538643.5 | c.181-1528C>T | intron_variant | 1 | |||||
MED25 | ENST00000593767.3 | c.418C>T | p.Arg140Trp | missense_variant | 5/18 | 3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251360Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135862
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461742Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727182
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74308
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 140 of the MED25 protein (p.Arg140Trp). This variant is present in population databases (rs781140315, gnomAD 0.006%). This missense change has been observed in individual(s) with MED25-related conditions (PMID: 25527630). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183670). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 23, 2024 | This substitution has been identified and confirmed in compound heterozygosity with a nonsense variant in a proband presenting neurodevelopmental delay, epilepsy and dysmorphic features reminiscent of Basel-Vanagaite-Smirin-Yosef syndrome (Mendelics). It is present at a very low frequency in gnomAD database - MAF 0.00002169 (v4.1.0) and has been previously described in the medical literature in homozygosity segregating with intellectual deficiency in seven individuals from a highly consanguineous Brazilian family (PMID: 25527630). - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Feb 01, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at