rs1556337063
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM2PM5PP2PP5_Very_StrongBP4
The ENST00000374080.8(MED12):c.3884G>A(p.Arg1295His) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,459 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign 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. R1295C) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000374080.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MED12 | NM_005120.3 | c.3884G>A | p.Arg1295His | missense_variant | 28/45 | ENST00000374080.8 | NP_005111.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MED12 | ENST00000374080.8 | c.3884G>A | p.Arg1295His | missense_variant | 28/45 | 1 | NM_005120.3 | ENSP00000363193 | P4 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD4 exome AF: 9.13e-7 AC: 1AN: 1095459Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 361059
GnomAD4 genome Cov.: 24
ClinVar
Submissions by phenotype
FG syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1295 of the MED12 protein (p.Arg1295His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked recessive MED12-related conditions (PMID: 23506379, 28369444, 30729724, 36271811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 521365). 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 not expected to disrupt MED12 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MED12 function (PMID: 28369444). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2021 | Segregated in an affected hemizygous brother in one family, and a heterozygous mother with moderate learning difficulties, skeletal and dysmorphic features, mitral valve prolapse, and skewed X-inactivation in another family (Callier et al., 2013; Donnio et al., 2017; Srivastava et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; A different missense change at this residue (R1295C) has been reported in the published literature in association with MED12-related disorders (Hu et al., 2016; Charzewska et al., 2018; Rubinato et al., 2019); This variant is associated with the following publications: (PMID: 31536828, 25644381, 33925166, 23506379, 28369444, 30729724) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, flagged submission | clinical testing | Ambry Genetics | Oct 25, 2016 | - - |
FG syndrome 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | Reported in persons with nonspecific intellectual disability and features of Lujan syndrome and in male sibs with features of FG syndrome type 1 and Lujan syndrome - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at