chr1-52397773-C-T

Variant names:

• chr1-52397773-C-T
• rs143141689
• NM_004153.4:c.314G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM5 PP5_Very_Strong BS1_Supporting

The NM_004153.4(ORC1):​c.314G>A​(p.Arg105Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000358082: Functional studies suggest that the p.Arg105Gln variant abolishes the ability of Orc1 to inhibit Cyclin E-CDK2 kinase activity (Hossain and Stillman 2012) and reduces DNA binding affinity leading to impaired nucleosome interaction (Zhang et al. 2015)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.58
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000358082: Functional studies suggest that the p.Arg105Gln variant abolishes the ability of Orc1 to inhibit Cyclin E-CDK2 kinase activity (Hossain and Stillman 2012) and reduces DNA binding affinity leading to impaired nucleosome interaction (Zhang et al. 2015).; SCV000711967: "In vitro functional studies provide some evidence that the p.Arg105Gln variant may impact protein function (Bicknell 2011, Hossain 2012, Zhang 2015)."; SCV001581768: Experimental studies have shown that this missense change affects ORC1 function (PMID: 22855792).; SCV001982423: Published functional studies demonstrate reduced ORC1 DNA binding affinity, leading to impaired ORC1-nucleosome reaction and a defect in regulation of centriole and centrosome copy numbers (PMID: 25689043, 22855792); SCV002064351: Functional studies indicates p.Arg105Gln disrupts the function of the ORC1 protein (PMID: 22855792, 25689043).; SCV005460889: "In multiple assays testing ORC1 function, this variant showed functionally abnormal results" (Hossain, 2012; Zhang, 2015)
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-52397774-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 982308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-52397773-C-T is Pathogenic according to our data. Variant chr1-52397773-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000312 (456/1461834) while in subpopulation NFE AF = 0.000375 (417/1111952). AF 95% confidence interval is 0.000344. There are 0 homozygotes in GnomAdExome4. There are 207 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004153.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	NM_004153.4	MANE Select	c.314G>A	p.Arg105Gln	missense	Exon 4 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.314G>A	p.Arg105Gln	missense	Exon 4 of 17	NP_001177747.1	Q13415
	ORC1	NM_001190819.2		c.314G>A	p.Arg105Gln	missense	Exon 4 of 17	NP_001177748.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	ENST00000371568.8	TSL:1 MANE Select	c.314G>A	p.Arg105Gln	missense	Exon 4 of 17	ENSP00000360623.3	Q13415
	ORC1	ENST00000371566.1	TSL:1	c.314G>A	p.Arg105Gln	missense	Exon 4 of 17	ENSP00000360621.1	Q13415
	ORC1	ENST00000959732.1		c.314G>A	p.Arg105Gln	missense	Exon 3 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000954 AC: 24 AN: 251480 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000312 AC: 456 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.000285 AC XY: 207 AN XY: 727224

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000375 AC: 417 AN: 1111952

Other (OTH) AF: 0.000596 AC: 36 AN: 60396

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Meier-Gorlin syndrome 1 (4)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Meier-Gorlin syndrome (1)
1	-	-	ORC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.72
Sift	Benign	0.087	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.57
MVP		0.92
MPC		0.67
ClinPred		0.46	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.61
Mutation Taster		=38/62	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs143141689; hg19: chr1-52863445;