1-42746753-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_022356.4(P3H1):βc.2154delCβ(p.Glu719AsnfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000386 in 1,553,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P718P) has been classified as Likely benign.
Frequency
Consequence
NM_022356.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000357 AC: 5AN: 1401672Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2AN XY: 691564
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74254
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type 8 Pathogenic:2
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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). For these reasons, this variant has been classified as Pathogenic. This frameshift has been observed in individual(s) with osteogenesis imperfecta (PMID: 24498616). This sequence change results in a frameshift in the P3H1 gene (p.Glu719Asnfs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the P3H1 protein and extend the protein by 10 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at