rs34644009
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004153.4(ORC1):c.2226C>A(p.Ser742=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,614,130 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0023 ( 10 hom. )
Consequence
ORC1
NM_004153.4 synonymous
NM_004153.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.424
Genes affected
ORC1 (HGNC:8487): (origin recognition complex subunit 1) The origin recognition complex (ORC) is a highly conserved six subunits protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is the largest subunit of the ORC complex. While other ORC subunits are stable throughout the cell cycle, the levels of this protein vary during the cell cycle, which has been shown to be controlled by ubiquitin-mediated proteolysis after initiation of DNA replication. This protein is found to be selectively phosphorylated during mitosis. It is also reported to interact with MYST histone acetyltransferase 2 (MyST2/HBO1), a protein involved in control of transcription silencing. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
?
Variant 1-52375507-G-T is Benign according to our data. Variant chr1-52375507-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 436112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00272 (414/152286) while in subpopulation AMR AF= 0.00601 (92/15302). AF 95% confidence interval is 0.00502. There are 2 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ORC1 | NM_004153.4 | c.2226C>A | p.Ser742= | synonymous_variant | 15/17 | ENST00000371568.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ORC1 | ENST00000371568.8 | c.2226C>A | p.Ser742= | synonymous_variant | 15/17 | 1 | NM_004153.4 | P1 | |
ORC1 | ENST00000371566.1 | c.2226C>A | p.Ser742= | synonymous_variant | 15/17 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00272 AC: 414AN: 152168Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00274 AC: 690AN: 251474Hom.: 3 AF XY: 0.00266 AC XY: 361AN XY: 135912
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GnomAD4 exome AF: 0.00230 AC: 3357AN: 1461844Hom.: 10 Cov.: 32 AF XY: 0.00230 AC XY: 1672AN XY: 727216
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GnomAD4 genome ? AF: 0.00272 AC: 414AN: 152286Hom.: 2 Cov.: 32 AF XY: 0.00270 AC XY: 201AN XY: 74460
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ORC1: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 08, 2019 | - - |
Meier-Gorlin syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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