19-49830790-C-T
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_030973.4(MED25):c.1004C>T(p.Ala335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 1,613,014 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A335T) has been classified as Uncertain significance.
Frequency
Consequence
NM_030973.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED25 | NM_030973.4 | c.1004C>T | p.Ala335Val | missense_variant | 9/18 | ENST00000312865.10 | |
MED25 | NM_001378355.1 | c.1004C>T | p.Ala335Val | missense_variant | 9/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED25 | ENST00000312865.10 | c.1004C>T | p.Ala335Val | missense_variant | 9/18 | 1 | NM_030973.4 | ||
MED25 | ENST00000538643.5 | c.365C>T | p.Ala122Val | missense_variant | 4/13 | 1 | |||
MED25 | ENST00000595185.5 | c.688+842C>T | intron_variant | 1 | |||||
MED25 | ENST00000593767.3 | c.1004C>T | p.Ala335Val | missense_variant | 9/18 | 3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00427 AC: 650AN: 152110Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00384 AC: 952AN: 247818Hom.: 3 AF XY: 0.00384 AC XY: 517AN XY: 134684
GnomAD4 exome AF: 0.00690 AC: 10082AN: 1460786Hom.: 41 Cov.: 33 AF XY: 0.00672 AC XY: 4886AN XY: 726696
GnomAD4 genome ? AF: 0.00428 AC: 651AN: 152228Hom.: 3 Cov.: 32 AF XY: 0.00395 AC XY: 294AN XY: 74424
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MED25: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 15, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Charcot-Marie-Tooth disease type 2B2 Uncertain:1Other:1
Uncertain significance, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2023 | - - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 14, 2020 | - - |
Charcot-Marie-Tooth disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
MED25-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 15, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at