1-52374887-C-T

Variant names:

• chr1-52374887-C-T
• rs61753389
• NM_004153.4:c.2314G>A

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.2314G>A​(p.Val772Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00579 in 1,612,708 control chromosomes in the GnomAD database, including 40 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V772L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (39 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -1.02
• Publications: 8 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=0.0065743923).
• BP6: Variant 1-52374887-C-T is Benign according to our data. Variant chr1-52374887-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297579.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 = 0.00475 (724/152282) while in subpopulation NFE AF = 0.00657 (447/68026). AF 95% confidence interval is 0.00607. There are 1 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 39 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.2314G>A	p.Val772Ile	missense	Exon 16 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.2314G>A	p.Val772Ile	missense	Exon 16 of 17	NP_001177747.1	Q13415
	ORC1	NM_001190819.2		c.2299G>A	p.Val767Ile	missense	Exon 16 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.2314G>A	p.Val772Ile	missense	Exon 16 of 17	ENSP00000360623.3	Q13415
	ORC1	ENST00000371566.1	TSL:1	c.2314G>A	p.Val772Ile	missense	Exon 16 of 17	ENSP00000360621.1	Q13415
	ORC1	ENST00000959732.1		c.2314G>A	p.Val772Ile	missense	Exon 15 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 723 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00489 AC: 1228 AN: 251312 AF XY: 0.00498

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00590 AC: 8620 AN: 1460426 Hom.: 39 Cov.: 30 AF XY: 0.00574 AC XY: 4170 AN XY: 726668

African (AFR) AF: 0.000837 AC: 28 AN: 33450

American (AMR) AF: 0.00141 AC: 63 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86232

European-Finnish (FIN) AF: 0.0168 AC: 895 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00661 AC: 7337 AN: 1110702

Other (OTH) AF: 0.00459 AC: 277 AN: 60344

GnomAD4 genome AF: 0.00475 AC: 724 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00500 AC XY: 372 AN XY: 74460

African (AFR) AF: 0.00103 AC: 43 AN: 41556

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00657 AC: 447 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00476 Hom.: 4

Bravo AF: 0.00339

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00455 AC: 552

EpiCase AF: 0.00562

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Meier-Gorlin syndrome 1 (3)
-	-	1	not specified (1)
-	-	1	ORC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.84
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.0
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.047
Sift	Benign	0.46	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.077
MVP		0.17
MPC		0.12
ClinPred		0.0046	T
GERP RS		-0.62
Varity_R		0.076
gMVP		0.067
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: rs61753389; hg19: chr1-52840559; COSMIC: COSV99056456;