rs61753390

Variant names:

• chr1-52393719-G-A
• rs61753390
• NM_004153.4:c.806C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004153.4(ORC1):​c.806C>T​(p.Ser269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00856 in 1,613,970 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S269S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (79 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.54
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006951213).
• BP6: Variant 1-52393719-G-A is Benign according to our data. Variant chr1-52393719-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00638 (971/152230) while in subpopulation NFE AF = 0.00778 (529/68016). AF 95% confidence interval is 0.00723. There are 12 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	NM_004153.4	MANE Select	c.806C>T	p.Ser269Leu	missense	Exon 6 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.806C>T	p.Ser269Leu	missense	Exon 6 of 17	NP_001177747.1
	ORC1	NM_001190819.2		c.806C>T	p.Ser269Leu	missense	Exon 6 of 17	NP_001177748.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	ENST00000371568.8	TSL:1 MANE Select	c.806C>T	p.Ser269Leu	missense	Exon 6 of 17	ENSP00000360623.3
	ORC1	ENST00000371566.1	TSL:1	c.806C>T	p.Ser269Leu	missense	Exon 6 of 17	ENSP00000360621.1

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152112 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00478

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00778

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00636 AC: 1590 AN: 249994 AF XY: 0.00625

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00878 AC: 12839 AN: 1461740 Hom.: 79 Cov.: 32 AF XY: 0.00874 AC XY: 6353 AN XY: 727166

African (AFR) AF: 0.00146 AC: 49 AN: 33462

American (AMR) AF: 0.00199 AC: 89 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00379 AC: 327 AN: 86220

European-Finnish (FIN) AF: 0.0216 AC: 1155 AN: 53410

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00964 AC: 10723 AN: 1111972

Other (OTH) AF: 0.00752 AC: 454 AN: 60386

GnomAD4 genome AF: 0.00638 AC: 971 AN: 152230 Hom.: 12 Cov.: 32 AF XY: 0.00701 AC XY: 522 AN XY: 74418

African (AFR) AF: 0.00144 AC: 60 AN: 41550

American (AMR) AF: 0.00425 AC: 65 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00437 AC: 21 AN: 4808

European-Finnish (FIN) AF: 0.0256 AC: 271 AN: 10596

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00778 AC: 529 AN: 68016

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00682 Hom.: 11

Bravo AF: 0.00493

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00557 AC: 676

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00782

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Meier-Gorlin syndrome 1 (2)
-	-	1	not specified (1)
-	-	1	ORC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.30
MVP		0.72
MPC		0.36
ClinPred		0.026	T
GERP RS		4.3
Varity_R		0.061
gMVP		0.30
Mutation Taster		=99/1	polymorphism

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: rs61753390; hg19: chr1-52859391;