chrX-71121602-G-A
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_005120.3(MED12):c.887G>A(p.Arg296Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296W) has been classified as Uncertain significance.
Frequency
Consequence
NM_005120.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MED12 | NM_005120.3 | c.887G>A | p.Arg296Gln | missense_variant | 7/45 | ENST00000374080.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MED12 | ENST00000374080.8 | c.887G>A | p.Arg296Gln | missense_variant | 7/45 | 1 | NM_005120.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Blepharophimosis - intellectual disability syndrome, MKB type Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Sep 21, 2023 | PS4, PM2, PP3, PP5 - The variant has been reported in ClinVar by other laboratories (Variation ID 1069251). This missense change has been observed in individual(s) with MED12 X-linked recessive associated conditions (PMID: 34573309). Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University | Oct 02, 2023 | This missense variant is absent from controls (PM2), and mRNA level analysis showed splicing variant causing 14 aminoacids inframe deletion in LCEWAV domain (NM_005120.3:r.847_888del ) (PM4) at the same time of missense effect p.Arg296Gln. This variant was cosegregated with both affected brothers and carrier mother (PP1), and symptoms were consistent with X-linked Ohdo syndrome (PP4). Multiple lines of computational evidence support a deleterious effect as CADD phred score is 31 (PP3), also previously reported as likely-pathogenic in ClinVae (PP5). This variant It is judged to be likely-pathogenic according to ACMG Guidelines, 2015. - |
FG syndrome 1 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | Reported in persons with X-linked Ohdo syndrome and nonspecific intellectual disability - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000522111). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2017 | - - |
FG syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MED12 protein function. ClinVar contains an entry for this variant (Variation ID: 522111). This missense change has been observed in individual(s) with MED12 X-linked recessive associated conditions (PMID: 27500536, 28794916, 34573309). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 296 of the MED12 protein (p.Arg296Gln). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20301719, 28794916, 31536828, 34573309, 27500536, 27620904, 32682435) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at