17-50192993-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000088.4(COL1A1):c.1821+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
NM_000088.4 splice_donor, intron
NM_000088.4 splice_donor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.54
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012059158 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-50192993-C-T is Pathogenic according to our data. Variant chr17-50192993-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 425580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50192993-C-T is described in Lovd as [Pathogenic]. Variant chr17-50192993-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COL1A1 | NM_000088.4 | c.1821+1G>A | splice_donor_variant, intron_variant | ENST00000225964.10 | NP_000079.2 | |||
| COL1A1 | XM_011524341.2 | c.1623+1G>A | splice_donor_variant, intron_variant | XP_011522643.1 | ||||
| COL1A1 | XM_005257058.5 | c.1821+1G>A | splice_donor_variant, intron_variant | XP_005257115.2 | ||||
| COL1A1 | XM_005257059.5 | c.958-300G>A | intron_variant | XP_005257116.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1993 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425580). This variant is also known as IVS26+1G>A. Disruption of this splice site has been observed in individuals with osteogenesis imperfecta (PMID: 8408653, 9067755, 10931857, 15931785, 17078022). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the COL1A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Dec 06, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease (Stover et al., 1993); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25944380, 8408653, 25525159, 10931857, 9295084, 7942841, 9443882, 30614853, 9067755, 28810924, 33470886, 33939306, 17078022, 15931785) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 23, 2018 | - - |
Osteogenesis imperfecta Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Apr 10, 2022 | The c.1821+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8408653) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:425580; PMID: 33939306; PMID: 33928192; PMID: 28810924; PMID: 32166892) - PS4. This variant is not present in population databases (rs66555264- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 33928192; 33228694) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic - |
Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029458:Postmenopausal osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
COL1A1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 13, 2023 | The COL1A1 c.1821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported to be causative for osteogenesis imperfecta (Stover et al. 1993. PubMed ID: 8408653; Zhytnik et al. 2020. PubMed ID: 32166892; Higuchi et al. 2021. PubMed ID: 33939306). mRNA studies showed that this variant results in intron 26 retention leading to a frameshift and premature protein termination (Stover et al. 1993. PubMed ID: 8408653). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 02, 2024 | The c.1821+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 26 of the COL1A1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This mutation has been reported in multiple subjects with osteogenesis imperfecta (OI) including a de novo occurrence (Körkkö J et al. Hum Mutat, 1997;9:148-56; Stover ML et al. J Clin Invest, 1993 Oct;92:1994-2002; Higuchi Y et al. Mol Genet Genomic Med, 2021 Jun;9:e1675; Holtz AP et al. Bone, 2023 Apr;169:116683; Mei Y et al. Front Endocrinol (Lausanne), 2022 Jul;13:935905). This variant has also been reported to segregate with disease in two families with OI (Zhytnik L et al. BMC Med Genomics, 2020 Nov;13:177; Doolan E et al. BMJ Open Ophthalmol, 2021 Apr;6:e000684). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -3
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at