rs193922149
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2
The NM_000088.4(COL1A1):βc.2450delβ(p.Pro817LeufsTer291) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000697 in 1,435,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P817P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000088.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.2450del | p.Pro817LeufsTer291 | frameshift_variant, splice_region_variant | 35/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.2252del | p.Pro751LeufsTer291 | frameshift_variant, splice_region_variant | 32/48 | ||
COL1A1 | XM_005257058.5 | c.2450del | p.Pro817LeufsTer201 | frameshift_variant, splice_region_variant | 35/49 | ||
COL1A1 | XM_005257059.5 | c.1532del | p.Pro511LeufsTer291 | frameshift_variant, splice_region_variant | 22/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.2450del | p.Pro817LeufsTer291 | frameshift_variant, splice_region_variant | 35/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000494334.1 | n.377del | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000697 AC: 10AN: 1435646Hom.: 0 Cov.: 32 AF XY: 0.00000559 AC XY: 4AN XY: 715284
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Osteogenesis imperfecta Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Pro817Leufs*291) 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 individual(s) with osteogenesis imperfecta (PMID: 27059743, 27748872). ClinVar contains an entry for this variant (Variation ID: 35912). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at