rs72651634
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000088.4(COL1A1):c.2010del(p.Gly671AlafsTer95) variant causes a frameshift change involving the alteration of a non-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. P670P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
NM_000088.4 frameshift
NM_000088.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.490
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 17-50191997-CA-C is Pathogenic according to our data. Variant chr17-50191997-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 497350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50191997-CA-C is described in Lovd as [Pathogenic]. Variant chr17-50191997-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.2010del | p.Gly671AlafsTer95 | frameshift_variant | 30/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.1812del | p.Gly605AlafsTer95 | frameshift_variant | 27/48 | ||
COL1A1 | XM_005257058.5 | c.2010del | p.Gly671AlafsTer95 | frameshift_variant | 30/49 | ||
COL1A1 | XM_005257059.5 | c.1092del | p.Gly365AlafsTer95 | frameshift_variant | 17/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.2010del | p.Gly671AlafsTer95 | frameshift_variant | 30/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000476387.1 | n.359del | non_coding_transcript_exon_variant | 6/9 | 2 | ||||
COL1A1 | ENST00000504289.1 | n.442del | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 44
GnomAD4 exome
Cov.:
44
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 30, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 22, 2022 | PM2_supporting, PS4_moderate, PVS1 - |
Osteogenesis imperfecta, perinatal lethal Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 2023 | ClinVar contains an entry for this variant (Variation ID: 497350). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with osteogenesis imperfecta type I (PMID: 11317364; Invitae). This sequence change creates a premature translational stop signal (p.Gly671Alafs*95) 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at