chrX-71130051-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP2PP5_Very_StrongBP4
The NM_005120.3(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 (★★).
Frequency
Consequence
NM_005120.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
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
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The c.3884G>A (p.R1295H) alteration is located in exon 28 (coding exon 28) of the MED12 gene. This alteration results from a G to A substitution at nucleotide position 3884, causing the arginine (R) at amino acid position 1295 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation, has been identified in individuals with features consistent with MED12-related disorder, and segregated with disease in at least one family (Donnio, 2017; Srivastava, 2019; Maia, 2023; Callier, 2013; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
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) -
FG syndrome Pathogenic:1
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. -
FG syndrome 1 Other:1
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