rs3087473

chr1-52402167-C-G

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.57G>C(p.Arg19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 1,614,162 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (41 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.214

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=0.005469382).
• BP6: Variant 1-52402167-C-G is Benign according to our data. Variant chr1-52402167-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 259242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-52402167-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (680/152324) while in subpopulation NFE AF= 0.00785 (534/68028). AF 95% confidence interval is 0.0073. There are 1 homozygotes in gnomad4. There are 288 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC1	NM_004153.4	c.57G>C	p.Arg19Ser	missense_variant	2/17	ENST00000371568.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC1	ENST00000371568.8	c.57G>C	p.Arg19Ser	missense_variant	2/17	1	NM_004153.4	P1
ORC1	ENST00000371566.1	c.57G>C	p.Arg19Ser	missense_variant	2/17	1		P1

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152206 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00421 AC: 1059 AN: 251446 Hom.: 6 AF XY: 0.00422 AC XY: 574 AN XY: 135892

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00700 AC: 10240 AN: 1461838 Hom.: 41 Cov.: 31 AF XY: 0.00671 AC XY: 4883 AN XY: 727226

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.00862

Gnomad4 OTH exome AF: 0.00532

GnomAD4 genome AF: 0.00446 AC: 680 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.00387 AC XY: 288 AN XY: 74486

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00690 Hom.: 4

Bravo AF: 0.00478

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00411 AC: 499

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ORC1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 15, 2016

- -

Meier-Gorlin syndrome 1 Benign:1

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. -

ORC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 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	0.19
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.095	N
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.046
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.058	T;T
Polyphen		0.016	B;B
Vest4		0.10
MutPred		0.34		Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);
MVP		0.53
MPC		0.17
ClinPred		0.0055	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.41

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: rs3087473; hg19: chr1-52867839;