ORC4

origin recognition complex subunit 4, the group of Origin recognition complex |AAA ATPases

Basic information

Region (hg38): 2:147930396-148021604

Previous symbols: [ "ORC4L" ]

Links

ENSG00000115947 ∙ NCBI:5000 ∙ OMIM:603056 ∙ HGNC:8490 ∙ Uniprot:O43929 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Meier-Gorlin syndrome 2 (Definitive), mode of inheritance: AR
• Meier-Gorlin syndrome 2 (Moderate), mode of inheritance: AR
• Meier-Gorlin syndrome 2 (Strong), mode of inheritance: AR
• Meier-Gorlin syndrome (Supportive), mode of inheritance: AD
• Meier-Gorlin syndrome 2 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Meier-Gorlin syndrome 2	AR	General	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	Craniofacial; Musculoskeletal	11477602; 21358632; 21358631; 22333897

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ORC4 gene.

• not provided (11 variants)
• Meier-Gorlin syndrome 2 (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ORC4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				18	1	19
missense		2	65	3	2	72
nonsense	4		1			5
start loss	1					1
frameshift	9		1			10
inframe indel						0
splice donor/acceptor (+/-2bp)		1				1
splice region			8	7	1	16
non coding			1	23	17	41
Total	14	3	68	44	20

Highest pathogenic variant AF is 0.00000775

Variants in ORC4

This is a list of pathogenic ClinVar variants found in the ORC4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-147935546-C-T			Likely benign (Mar 18, 2023)
2-147935581-C-G			Uncertain significance (May 12, 2022)
2-147935594-AG-A		Meier-Gorlin syndrome 2	Pathogenic (Sep 16, 2014)
2-147935619-A-G		Inborn genetic diseases	Uncertain significance (May 28, 2024)
2-147935626-ACT-A			Uncertain significance (Apr 05, 2023)
2-147935635-G-C			Uncertain significance (Aug 31, 2022)
2-147935658-A-T			Uncertain significance (Feb 17, 2022)
2-147935659-T-C			Uncertain significance (Jan 26, 2022)
2-147935670-A-G			Uncertain significance (Aug 27, 2020)
2-147935680-G-T		Inborn genetic diseases	Uncertain significance (Nov 07, 2024)
2-147935685-A-G		not specified • Inborn genetic diseases	Uncertain significance (Jan 08, 2024)
2-147935704-A-G			Likely benign (Dec 20, 2022)
2-147935712-G-T			Benign (Dec 25, 2023)
2-147938135-CTA-C			Likely benign (Sep 27, 2023)
2-147938138-AATCTT-A			Uncertain significance (Nov 08, 2022)
2-147938157-C-T			Uncertain significance (Feb 05, 2022)
2-147938163-T-A			Uncertain significance (Jul 12, 2022)
2-147938178-C-T		not specified • Inborn genetic diseases • ORC4-related disorder	Conflicting classifications of pathogenicity (Jul 05, 2024)
2-147938188-T-C			Likely benign (Jan 18, 2024)
2-147938200-A-G			Likely benign (Mar 20, 2020)
2-147938228-A-G			Uncertain significance (Feb 24, 2023)
2-147938229-T-C			Likely benign (Oct 05, 2022)
2-147938278-C-G			Likely benign (Feb 01, 2023)
2-147938284-A-C			Likely benign (Dec 25, 2023)
2-147938290-C-T			Likely benign (Nov 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ORC4	protein_coding	protein_coding	ENST00000392857	13	91180

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.57e-13	0.234	125674	0	66	125740	0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.203	231	222	1.04	0.0000110	2878
Missense in Polyphen		71	68.519	1.0362		883
Synonymous	0.997	65	76.1	0.855	0.00000365	767
Loss of Function	1.02	22	27.8	0.791	0.00000141	341

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000632	0.000630
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000382	0.000381
Finnish	0.00	0.00
European (Non-Finnish)	0.000276	0.000273
Middle Eastern	0.000382	0.000381
South Asian	0.000365	0.000359
Other	0.000164	0.000163

dbNSFP

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. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3. {ECO:0000269|PubMed:22427655}.
• Disease: DISEASE: Meier-Gorlin syndrome 2 (MGORS2) [MIM:613800]: 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:21358631, ECO:0000269|PubMed:21358632}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cell cycle - Homo sapiens (human);Cell Cycle;G1 to S cell cycle control;DNA Replication;cdk regulation of dna replication;Activation of ATR in response to replication stress;G2/M Checkpoints;Cell Cycle Checkpoints;Activation of the pre-replicative complex;E2F mediated regulation of DNA replication;Mitotic G1-G1/S phases;Orc1 removal from chromatin;DNA Replication;Switching of origins to a post-replicative state;Synthesis of DNA;S Phase;G1/S Transition;E2F-enabled inhibition of pre-replication complex formation;Assembly of the ORC complex at the origin of replication;CDC6 association with the ORC:origin complex;CDT1 association with the CDC6:ORC:origin complex;Assembly of the pre-replicative complex;DNA Replication Pre-Initiation;M/G1 Transition;Cell Cycle;Cell Cycle, Mitotic (Consensus)

Recessive Scores

• pRec: 0.119

Intolerance Scores

• rvis_EVS: 0.82
• rvis_percentile_EVS: 87.95

Haploinsufficiency Scores

• pHI: 0.767
• hipred: Y
• hipred_score: 0.610
• ghis: 0.531

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: N
• gene_indispensability_score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Orc4

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;DNA replication;DNA replication initiation
• Cellular component: nuclear chromosome, telomeric region;origin recognition complex;nucleus;nucleoplasm;nuclear origin of replication recognition complex;nucleolus;cytosol
• Molecular function: nucleotide binding;DNA replication origin binding;protein binding;ATP binding