rs875989806
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_005120.3(MED12):c.1562G>A(p.Arg521His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,109 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R521C) has been classified as Uncertain significance.
Frequency
Consequence
NM_005120.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED12 | NM_005120.3 | c.1562G>A | p.Arg521His | missense_variant | 11/45 | ENST00000374080.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED12 | ENST00000374080.8 | c.1562G>A | p.Arg521His | missense_variant | 11/45 | 1 | NM_005120.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 exomes AF: 0.00000550 AC: 1AN: 181798Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67626
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1098109Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 363467
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | literature only | Center for Human Genetics, University of Leuven | Jan 01, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27159028, 28369444, 26813965) - |
MED12-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | The MED12 c.1562G>A variant is predicted to result in the amino acid substitution p.Arg521His. This variant has been reported as de novo in a female with intellectual disability and significantly skewed X inactivation (Fieremans et al. 2016. PubMed ID: 27159028). This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at