chr19-29702977-C-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001282929.1(C19orf12):c.-32G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001282929.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249090Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134842
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461878Hom.: 0 Cov.: 37 AF XY: 0.0000179 AC XY: 13AN XY: 727238
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Global developmental delay;C3714756:Intellectual disability Pathogenic:1
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Neurodegeneration with brain iron accumulation 4 Pathogenic:1
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not provided Pathogenic:1
The c.194 G>T variant in the C19orf12 gene has been previously reported in the homozygous state, and in the presence of a loss of function C19orf12 variant, in two unrelated sets of affected siblings with mitochondrial membrane protein-associated neurodegeneration (MPAN) (Hogarth et al., 2013; Yoganathan et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico splice prediction models predict that c.194 G>T may weaken the natural splice acceptor site for intron 2. However, in the absence of RNA/functional studies, the effect of the c.194 G>T change in this individual is unknown. If c.194 G>T does not alter splicing, it will result in the G65V missense change. The G65V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position within a transmembrane domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret the c.194 G>T variant as a likely pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at