1-52373187-G-A

Variant names:

• chr1-52373187-G-A
• rs61756139
• NM_004153.4:c.2580C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004153.4(ORC1):​c.2580C>T​(p.Asp860Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,052 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (2 hom.)
• Consequence: ORC1 NM_004153.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.47
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-52373187-G-A is Benign according to our data. Variant chr1-52373187-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 703217.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000663 (101/152304) while in subpopulation SAS AF = 0.00125 (6/4818). AF 95% confidence interval is 0.000834. There are 1 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.2580C>T	p.Asp860Asp	synonymous	Exon 17 of 17	NP_004144.2
	ORC1	NM_001190818.2		c.2580C>T	p.Asp860Asp	synonymous	Exon 17 of 17	NP_001177747.1	Q13415
	ORC1	NM_001190819.2		c.2565C>T	p.Asp855Asp	synonymous	Exon 17 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.2580C>T	p.Asp860Asp	synonymous	Exon 17 of 17	ENSP00000360623.3	Q13415
	ORC1	ENST00000371566.1	TSL:1	c.2580C>T	p.Asp860Asp	synonymous	Exon 17 of 17	ENSP00000360621.1	Q13415
	ORC1	ENST00000959732.1		c.2580C>T	p.Asp860Asp	synonymous	Exon 16 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152186 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000835 AC: 210 AN: 251472 AF XY: 0.000795

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.000870

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000628 AC: 918 AN: 1461748 Hom.: 2 Cov.: 31 AF XY: 0.000667 AC XY: 485 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00162 AC: 140 AN: 86252

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53406

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5734

European-Non Finnish (NFE) AF: 0.000537 AC: 597 AN: 1111936

Other (OTH) AF: 0.000613 AC: 37 AN: 60390

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152304 Hom.: 1 Cov.: 33 AF XY: 0.000671 AC XY: 50 AN XY: 74480

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68036

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

Alfa AF: 0.000701 Hom.: 1

Bravo AF: 0.000484

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.86
PhyloP100		-1.5
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: rs61756139; hg19: chr1-52838859; COSMIC: COSV65364679; COSMIC: COSV65364679;