rs72645369
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000088.4(COL1A1):c.1127delC(p.Pro376LeufsTer165) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000088.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.1127delC | p.Pro376LeufsTer165 | frameshift_variant | Exon 17 of 51 | ENST00000225964.10 | NP_000079.2 | |
COL1A1 | XM_005257058.5 | c.1127delC | p.Pro376LeufsTer165 | frameshift_variant | Exon 17 of 49 | XP_005257115.2 | ||
COL1A1 | XM_011524341.2 | c.958-117delC | intron_variant | Intron 14 of 47 | XP_011522643.1 | |||
COL1A1 | XM_005257059.5 | c.957+719delC | intron_variant | Intron 14 of 37 | XP_005257116.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:2
This sequence change creates a premature translational stop signal (p.Pro376Leufs*165) in the COL1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with osteogenesis imperfecta type I (PMID: 8808594). ClinVar contains an entry for this variant (Variation ID: 859292). For these reasons, this variant has been classified as Pathogenic. -
The variant c.1127delC (p.Pro376Leufs * 165) in the COL1A1 gene is reported as a pathogenic for osteogenesis imperfecta I in ClinVar (Variation ID: 859292). This variant creates a shift in the reading frame which is predicted to result in a premature stop codon 165 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no frequency information in the gnomAD or 1000 Genomes Project databases. -
Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1
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not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 8808594, 23729740) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at