rs2307397

Positions:

chr2-147972798-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181741.4(ORC4):c.166C>G(p.Leu56Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,610,564 control chromosomes in the GnomAD database, including 1,929 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L56F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 121 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1808 hom. )

Consequence

ORC4
NM_181741.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.152

Variant links:

Genes affected

ORC4 (HGNC:8490): (origin recognition complex subunit 4) The origin recognition complex (ORC) is a highly conserved six subunit 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. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]

ORC4 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=0.0019108951).

BP6

Variant 2-147972798-G-C is Benign according to our data. Variant chr2-147972798-G-C is described in ClinVar as [Benign]. Clinvar id is 159482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-147972798-G-C is described in Lovd as [Benign]. Variant chr2-147972798-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC4	NM_181741.4 linkuse as main transcript	c.166C>G	p.Leu56Val	missense_variant	4/14	ENST00000392857.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC4	ENST00000392857.10 linkuse as main transcript	c.166C>G	p.Leu56Val	missense_variant	4/14	1	NM_181741.4	P1	O43929-1

Frequencies

GnomAD3 genomes

AF:

0.0341

AC:

5183

AN:

152030

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00971

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0368

Gnomad ASJ

AF:

0.0548

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0218

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0522

Gnomad OTH

AF:

0.0513

GnomAD3 exomes

AF:

0.0370

AC:

9278

AN:

250956

Hom.:

222

AF XY:

0.0377

AC XY:

5115

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00979

Gnomad AMR exome

AF:

0.0270

Gnomad ASJ exome

AF:

0.0545

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0273

Gnomad FIN exome

AF:

0.0197

Gnomad NFE exome

AF:

0.0538

Gnomad OTH exome

AF:

0.0439

GnomAD4 exome

AF:

0.0466

AC:

68011

AN:

1458416

Hom.:

1808

Cov.:

AF XY:

0.0464

AC XY:

33666

AN XY:

725680

show subpopulations

Gnomad4 AFR exome

AF:

0.00922

Gnomad4 AMR exome

AF:

0.0290

Gnomad4 ASJ exome

AF:

0.0551

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0269

Gnomad4 FIN exome

AF:

0.0207

Gnomad4 NFE exome

AF:

0.0526

Gnomad4 OTH exome

AF:

0.0471

GnomAD4 genome

AF:

0.0341

AC:

5184

AN:

152148

Hom.:

121

Cov.:

AF XY:

0.0325

AC XY:

2414

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00968

Gnomad4 AMR

AF:

0.0368

Gnomad4 ASJ

AF:

0.0548

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0220

Gnomad4 FIN

AF:

0.0189

Gnomad4 NFE

AF:

0.0523

Gnomad4 OTH

AF:

0.0508

Alfa

AF:

0.0498

Hom.:

155

Bravo

AF:

0.0358

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0506

AC:

195

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0540

AC:

464

ExAC

AF:

0.0379

AC:

4602

Asia WGS

AF:

0.0170

AC:

AN:

3472

EpiCase

AF:

0.0561

EpiControl

AF:

0.0571

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.6

DANN

Benign

0.94

DEOGEN2

Benign

0.0038

T;T;T;T;.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.90

D;.;.;D;D;D

MetaRNN

Benign

0.0019

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.2

N;N;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

0.38

N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.29

T;T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;.;T;.

Polyphen

0.0

B;B;B;.;.;.

Vest4

0.015

MPC

0.093

ClinPred

0.0096

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.17

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