1-42746730-TGAGA-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_022356.4(P3H1):c.2174_2177delTCTC(p.Leu725GlnfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_022356.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000214 AC: 3AN: 1399858Hom.: 0 AF XY: 0.00000290 AC XY: 2AN XY: 690466
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type 8 Pathogenic:1Uncertain:2
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change results in a frameshift in the P3H1 gene (p.Leu725Glnfs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the P3H1 protein and extend the protein by 9 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with P3H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 800999). This variant disrupts the KDEL domain (p.Lys733-p.Leu736) of the P3H1 protein that is required for the cellular retention and activity of certain types of proteins (PMID: 3545499). -
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The frameshift variant c.2174_2177del (p.Leu725GlnfsTer22) in the P3H1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is absent in the gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Uncertain significance. This variant causes a frameshift starting with codon Leucine 725, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 22 of the new reading frame. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing (Essawi et al., 2018). However this variant is in last exon, further evidence is required to prove protein truncation. For these reasons, this variant has been classified as uncertained significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at