rs61753390

Positions:

chr1-52393719-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 (★★).

Frequency

Genomes: 𝑓 0.0064 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 79 hom. )

Consequence

ORC1
NM_004153.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.54

Variant links:

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]

ORC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC1	NM_004153.4 linkuse as main transcript	c.806C>T	p.Ser269Leu	missense_variant	6/17	ENST00000371568.8	NP_004144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC1	ENST00000371568.8 linkuse as main transcript	c.806C>T	p.Ser269Leu	missense_variant	6/17	1	NM_004153.4	ENSP00000360623	P1
ORC1	ENST00000371566.1 linkuse as main transcript	c.806C>T	p.Ser269Leu	missense_variant	6/17	1		ENSP00000360621	P1

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

974

AN:

152112

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00625

AC XY:

845

AN XY:

135284

show subpopulations

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.:

Cov.:

AF XY:

0.00874

AC XY:

6353

AN XY:

727166

show subpopulations

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.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74418

show subpopulations

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.:

Bravo

AF:

0.00493

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00557

AC:

676

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00782

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ORC1: BP4, BS2 -

Meier-Gorlin syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2021	- -
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. -

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, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

-0.026

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.73

.;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over