GeneBe

ORC6

protein-coding

origin recognition complex subunit 6, the group of Origin recognition complex

Gene summary

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. The protein encoded by this gene is a subunit of the ORC complex. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis. [provided by RefSeq, Oct 2010]

Previous symbols:
  • ORC6L

MANE transcript

NM_014321.4

Inheritance

AR, AD

ClinVar variants

P:19U:63B:42

Top phenotype

Meier-Gorlin syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr16:46,689,643-46,698,394

External References & Databases

Ensembl (ENSG00000091651)NCBI Gene (23594)OMIM (607213)HGNC:17151GenCCUniProt (Q9Y5N6)AlphaFoldClinVar (ORC6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Meier-Gorlin syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013430

Submitter: G2P

Meier-Gorlin syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013430

Submitter: ClinGen

The ORC6 gene is located on chromosome 16 at 16q11.2 and encodes origin recognition complex subunit 6. The origin recognition complex (ORC) assembles at origins of replication and recruits additional proteins of the pre-replication complex needed to initiate DNA replication (Klingseisen and Jackson, 2011, PMID: 21979914). ORC6 was first reported in relation to Meier-Gorlin syndrome 3 in 2011 (Bicknell et al., PMID: 21358632). Meier-Gorlin syndrome 3 is an autosomal recessive primordial dwarfism characterized by a clinical triad of ​patellar aplasia or hypoplasia, microtia, and prenatal-onset growth deficiency. Additional common features include microcephaly, cryptorchidism, breast agenesis, feeding problems, pulmonary emphysema, skeletal anomalies, and distinctive facial features described as microstomia, micrognathia, full lips, high forehead, and narrow nose with a high nasal bridge (Nielsen-Dandoroff et al., 2023, PMID:37059840). At least 3 missense, 1 splice region, 1 start-loss, and 1 nonsense variant have been reported in nine affected individuals in six families described in four publications and included in this curation (PMID: 21358632; De Munnik et al., 2012, PMID: 22333897; Nazarenko et al. 2022,, PMID: 36012502; Li et al., 2022, PMID: 34850017). This gene-disease relationship is also supported by experimental evidence of ORC6 biochemical function, protein interaction, functional alteration, and animal models (Prasanth et al., 2002, PMID: 12169736; Basalov et al., 2007, PMID: 17283052; Chen et al., 2007, PMID: 18006685; Basalov et al., 2009, PMID: 19541634; Basalov et al., 2015, PMID: 26139588; Basalov et al., 2020, PMID: 33037049). The proposed mechanism of disease is partial loss-of-function. In summary, there is definitive evidence supporting the relationship between ORC6 and Meier-Gorlin syndrome 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Syndromic Disorders GCEP on July 21, 2023 (SOP Version 9).

Meier-Gorlin syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013430

Submitter: Labcorp Genetics (formerly Invitae)

Meier-Gorlin syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013430

Submitter: PanelApp Australia

Meier-Gorlin syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016817

Submitter: Orphanet

Clinical Genomic Database (CGD)

Meier-Gorlin syndrome 3AR

Manifestation: Craniofacial; Genitourinary; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7710253; 21358632; 22333897Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ORC6 variants in ClinVar

5 Conditions Cataloged
not providedTotal: 104
Inborn genetic diseasesTotal: 41
Meier-Gorlin syndrome 3Total: 25
ORC6-related disorderTotal: 4
not specifiedTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014321.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
36
clinvar
 36
missense
3
clinvar
1
clinvar
63
clinvar
6
clinvar
 73
nonsense
3
clinvar
 3
start loss
2
clinvar
 2
frameshift
5
clinvar
1
clinvar
 6
splice donor/acceptor (+/-2bp)
4
clinvar
 4
Total13663420124

Highest pathogenic variant AF is 0.0005671632

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_014321.4RefSeqNP_055136.17MANE Select
ENST00000219097.7EnsemblENSP00000219097.27MANE Select
ENST00000563599.5EnsemblENSP00000454299.12Standard
ENST00000566860.1EnsemblENSP00000456981.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell cycle - Homo sapiens (human)
  • Cell Cycle
  • G1 to S cell cycle control
  • DNA Replication
  • cdk regulation of dna replication

Biological Process

  • G1/S transition of mitotic cell cycle
  • DNA replication
  • DNA replication initiation
  • negative regulation of cell division

Molecular Function

  • DNA replication origin binding
  • protein binding

Cellular Component

  • origin recognition complex
  • fibrillar center
  • nucleus
  • nucleoplasm
  • nuclear origin of replication recognition complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000219097
Coding exons
7
Length
8752
Individuals with no LoFs
125716
Homozygous LoFs
0
Heterozygous LoFs
32
Defined
125748
p
0.000127
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.4871511351.120.000006741631
Missense (PolyPhen)3737.0170.99955472
Synonymous-0.9535950.41.170.00000253489
Loss of Function0.5251113.00.8436.17e-7167

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American0.000120.000087rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000110.00011rare
Finnish0.0000930.000092rare
European (Non-Finnish)0.000170.00017rare
South Asian0.0000650.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre- replication complex necessary to initiate DNA replication. Does not bind histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3. {ECO:0000269|PubMed:22427655}.;
Disease
DISEASE: Meier-Gorlin syndrome 3 (MGORS3) [MIM:613803]: A syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. {ECO:0000269|PubMed:21358632}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.103

Intolerance Scores

RVIS EVS
-0.41
RVIS percentile EVS
26.23

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
N
Indispensability score
0.114

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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