rs72656314
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000088.4(COL1A1):c.3421C>T(p.Arg1141Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1141R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000088.4 stop_gained, splice_region
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.3421C>T | p.Arg1141Ter | stop_gained, splice_region_variant | 46/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.3223C>T | p.Arg1075Ter | stop_gained, splice_region_variant | 43/48 | ||
COL1A1 | XM_005257058.5 | c.3151C>T | p.Arg1051Ter | stop_gained, splice_region_variant | 44/49 | ||
COL1A1 | XM_005257059.5 | c.2503C>T | p.Arg835Ter | stop_gained, splice_region_variant | 33/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.3421C>T | p.Arg1141Ter | stop_gained, splice_region_variant | 46/51 | 1 | NM_000088.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 13, 2023 | The COL1A1 c.3421C>T; p.Arg1141Ter variant (rs72656314) is reported in the literature in individuals affected with osteogenesis imperfecta (Balasubramanian 2016, Bardai 2017, Chen 2022, Higuchi 1994, Mei 2022, Tuysuz 2022, Willing 1994). This variant is also reported in ClinVar (Variation ID: 17337), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Balasubramanian M et al. Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation. Ultrastruct Pathol. 2016;40(2):71-6. PMID: 26863094. Bardai G et al. Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta. Osteoporos Int. 2017 Jul;28(7):2095-2101. PMID: 28378289. Chen P et al. Phenotypic Spectrum and Molecular Basis in a Chinese Cohort of Osteogenesis Imperfecta With Mutations in Type I Collagen. Front Genet. 2022 Jan 28;13:816078. PMID: 35154279. Higuchi Y et al. Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands. Mol Genet Genomic Med. 2021 Jun;9(6):e1675. PMID: 33939306. Mei Y et al. Comparing Clinical and Genetic Characteristics of De Novo and Inherited COL1A1/COL1A2 Variants in a Large Chinese Cohort of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2022 Jul 14;13:935905. PMID: 35909573. Tuysuz B et al. Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1/A2 and biallelic variants. Bone. 2022 Feb;155:116293. PMID: 34902613. Willing MC et al. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am J Hum Genet. 1994 Oct;55(4):638-47. PMID: 7942841. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 23, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2022 | Nonsense 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7942841, 9067755, 25525159, 26863094, 25436829, 16879195, 25214535, 28882457, 18311573, 28378289, 16705691, 32123938, 33939306) - |
Osteogenesis imperfecta type I Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): 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 (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017337, PMID:7942841). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg1141*) 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: 7942841, 9067755, 16705691, 28378289). ClinVar contains an entry for this variant (Variation ID: 17337). For these reasons, this variant has been classified as Pathogenic. - |
Osteogenesis imperfecta Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jun 30, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at