NM_181741.4:c.166C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Meier-Gorlin syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 159482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ORC4	NM_181741.4 link	c.166C>G	p.Leu56Val	missense_variant	Exon 4 of 14	ENST00000392857.10	NP_859525.1	O43929-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10 link	c.166C>G	p.Leu56Val	missense_variant	Exon 4 of 14	1	NM_181741.4	ENSP00000376597.5		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

GnomAD2 exomes

AF:

0.0370

AC:

9278

AN:

250956

AF XY:

0.0377

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 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

African (AFR)

AF:

0.00922

AC:

308

AN:

33414

American (AMR)

AF:

0.0290

AC:

1297

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.0551

AC:

1436

AN:

26078

East Asian (EAS)

AF:

0.000151

AC:

AN:

39640

South Asian (SAS)

AF:

0.0269

AC:

2321

AN:

86178

European-Finnish (FIN)

AF:

0.0207

AC:

1102

AN:

53362

Middle Eastern (MID)

AF:

0.0599

AC:

345

AN:

5762

European-Non Finnish (NFE)

AF:

0.0526

AC:

58357

AN:

1109058

Other (OTH)

AF:

0.0471

AC:

2839

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

2671

5343

8014

10686

13357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2114

4228

6342

8456

10570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0341

AC:

5184

AN:

152148

Hom.:

121

Cov.:

AF XY:

0.0325

AC XY:

2414

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00968

AC:

402

AN:

41538

American (AMR)

AF:

0.0368

AC:

562

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

190

AN:

3466

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0220

AC:

106

AN:

4818

European-Finnish (FIN)

AF:

0.0189

AC:

200

AN:

10574

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0523

AC:

3552

AN:

67970

Other (OTH)

AF:

0.0508

AC:

107

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

257

514

771

1028

1285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

0.15

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

Mutation Taster

=293/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over