rs879255527
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005120.3(MED12):c.5898dupC(p.Ser1967GlnfsTer84) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005120.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The c.5898dupC variant in the MED12 gene has been reported previously in a family with intellectual disability and dysmorphic features and it is associated with mild to severe symptoms in both males and females (Lesca et al., 2013). The duplication causes a frameshift starting with codon Serine 1967, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 84 of the new reading frame, denoted p.Ser1967GlnfsX84. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, RNA expression studies show that the mutated allele was not degraded by nonsense-mediated RNA decay and induced an additional abnormal isoform due to activation of cryptic splice sites (Lesca et al., 2013). The c.5898dupC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
MED12-related intellectual disability syndrome Pathogenic:1
The hemizygous p.Ser1967GlnfsTer84 variant in MED12 was identified by our study in two affected members of one family with intellectual disability. The p.Ser1967GlnfsTer84 variant in MED12 has been previously reported in 11 affected members of one family with MED12-related disorder and segregated with disease in this family (PMID: 24039113). This variant has also been reported in ClinVar (Variation ID: 252964) and has been interpreted as likely pathogenic by GeneDx. This variant was absent from large population studies. RT-PCR analysis performed on affected tissue showed that while this variant does not result in nonsense mediated decay, it yields two alternative transcripts: one with a frameshift and the other with an in-frame 75 base pair deletion due to activation of 2 cryptic splice sites in exon 41 (PMID: 24039113). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1967 and leads to a premature termination codon 84 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MED12 gene is an established disease mechanism in MED12-related disorders. In summary, this variant meets criteria to be classified as pathogenic for MED12-related disorders. ACMG/AMP Criteria applied: PVS1_Strong, PS3_Moderate, PM2_Supporting, PP1_Strong (Richards 2015). -
FG syndrome 1 Other:1
Reported in males and females with nonspecific intellectual disability -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at