rs61753390

chr1-52393719-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004153.4(ORC1):c.806C>T(p.Ser269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00856 in 1,613,970 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S269S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (79 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006951213).
• BP6: Variant 1-52393719-G-A is Benign according to our data. Variant chr1-52393719-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-52393719-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00638 (971/152230) while in subpopulation NFE AF= 0.00778 (529/68016). AF 95% confidence interval is 0.00723. There are 12 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC1	NM_004153.4	c.806C>T	p.Ser269Leu	missense_variant	6/17	ENST00000371568.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC1	ENST00000371568.8	c.806C>T	p.Ser269Leu	missense_variant	6/17	1	NM_004153.4	P1
ORC1	ENST00000371566.1	c.806C>T	p.Ser269Leu	missense_variant	6/17	1		P1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152112 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00478

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00778

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00636 AC: 1590 AN: 249994 Hom.: 13 AF XY: 0.00625 AC XY: 845 AN XY: 135284

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00373

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00878 AC: 12839 AN: 1461740 Hom.: 79 Cov.: 32 AF XY: 0.00874 AC XY: 6353 AN XY: 727166

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00379

Gnomad4 FIN exome AF: 0.0216

Gnomad4 NFE exome AF: 0.00964

Gnomad4 OTH exome AF: 0.00752

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152230 Hom.: 12 Cov.: 32 AF XY: 0.00701 AC XY: 522 AN XY: 74418

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.00778

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00714 Hom.: 4

Bravo AF: 0.00493

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00557 AC: 676

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00782

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ORC1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Meier-Gorlin syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 29, 2016

- -

ORC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.51	D
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;D
Vest4		0.30
MVP		0.72
MPC		0.36
ClinPred		0.026	T
GERP RS		4.3
Varity_R		0.061
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61753390; hg19: chr1-52859391;