rs1555572401
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000225964.10(COL1A1):c.2908_2911del(p.Arg970AlafsTer137) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R970R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
ENST00000225964.10 frameshift
ENST00000225964.10 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.82
Genes affected
COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-50189193-CCTCT-C is Pathogenic according to our data. Variant chr17-50189193-CCTCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 456758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.2908_2911del | p.Arg970AlafsTer137 | frameshift_variant | 40/51 | ENST00000225964.10 | NP_000079.2 | |
COL1A1 | XM_005257059.5 | c.1990_1993del | p.Arg664AlafsTer137 | frameshift_variant | 27/38 | XP_005257116.2 | ||
COL1A1 | XM_011524341.2 | c.2710_2713del | p.Arg904AlafsTer137 | frameshift_variant | 37/48 | XP_011522643.1 | ||
COL1A1 | XM_005257058.5 | c.2668-187_2668-184del | intron_variant | XP_005257115.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.2908_2911del | p.Arg970AlafsTer137 | frameshift_variant | 40/51 | 1 | NM_000088.4 | ENSP00000225964 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 20, 2017 | For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 2794057). This sequence change deletes 4 nucleotide from exon 40 of the COL1A1 mRNA (c.2908_2911delAGAG), causing a frameshift at codon 970. This creates a premature translational stop signal (p.Arg970Alafs*137) and is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 27, 2020 | The COL1A1 c.2908_2911del variant is classified as a PATHOGENIC variant (PVS1, PM2, PP4) The COL1A1 c.2908_2911del deletes 4 nucleotides from exon 40 of the COL1A1 mRNA causing a frameshift at codon 970. This creates a premature translational stop signal (p.Arg970Alafs*137) and is expected to result in an absent or disrupted protein product. This variant has been reported in a patient with Osteogenesis imperfecta (PMID: 30715774) and other loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 2794057) (PVS1). The variant has been reported in ClinVar as pathogenic by another diagnostic laboratory (Variation ID: VCV000456758), and HGMD as damaging for Osteogenesis imperfecta (CD194665). The variant has not been reported in dbSNP and is absent from population databases (PM2). - |
Osteogenesis imperfecta type III Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. Similarly affected sibling shares the variant. The variant has been reported to be associated with COL1A1 related disorder (ClinVar ID: VCV000456758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at