rs3087483

Variant names:

• chr1-52385927-C-T
• rs3087483
• NM_004153.4:c.1406G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-52385927-C-T
• chr1-52385927-C-G

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.1406G>A​(p.Cys469Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,613,606 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. C469R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (15 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00100
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030913353).
• BP6: Variant 1-52385927-C-T is Benign according to our data. Variant chr1-52385927-C-T is described in ClinVar as Benign. ClinVar VariationId is 129857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1526/152272) while in subpopulation AFR AF = 0.0351 (1460/41566). AF 95% confidence interval is 0.0336. There are 20 homozygotes in GnomAd4. There are 718 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC1	NM_004153.4	MANE Select	c.1406G>A	p.Cys469Tyr	missense	Exon 9 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.1406G>A	p.Cys469Tyr	missense	Exon 9 of 17	NP_001177747.1	Q13415
	ORC1	NM_001190819.2		c.1391G>A	p.Cys464Tyr	missense	Exon 9 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.1406G>A	p.Cys469Tyr	missense	Exon 9 of 17	ENSP00000360623.3	Q13415
	ORC1	ENST00000371566.1	TSL:1	c.1406G>A	p.Cys469Tyr	missense	Exon 9 of 17	ENSP00000360621.1	Q13415
	ORC1	ENST00000959732.1		c.1406G>A	p.Cys469Tyr	missense	Exon 8 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1524 AN: 152154 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00250 AC: 627 AN: 251278 AF XY: 0.00183

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000918 AC: 1342 AN: 1461334 Hom.: 15 Cov.: 31 AF XY: 0.000785 AC XY: 571 AN XY: 726982

African (AFR) AF: 0.0331 AC: 1107 AN: 33450

American (AMR) AF: 0.00188 AC: 84 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: 0.0000696 AC: 6 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00130 AC: 7 AN: 5394

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111926

Other (OTH) AF: 0.00194 AC: 117 AN: 60360

GnomAD4 genome AF: 0.0100 AC: 1526 AN: 152272 Hom.: 20 Cov.: 32 AF XY: 0.00964 AC XY: 718 AN XY: 74454

African (AFR) AF: 0.0351 AC: 1460 AN: 41566

American (AMR) AF: 0.00301 AC: 46 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00381 Hom.: 16

Bravo AF: 0.0115

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Meier-Gorlin syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.37
DANN	Benign	0.39
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.0010
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.041
Sift	Benign	0.20	T
Sift4G	Uncertain	0.056	T
Polyphen		0.0020	B
Vest4		0.14
MVP		0.19
MPC		0.26
ClinPred		0.0021	T
GERP RS		-5.9
Varity_R		0.023
gMVP		0.24
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: rs3087483; hg19: chr1-52851599;