1-52372950-G-A

Position:

• chr1-52372950-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004153.4(ORC1):​c.*231C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 535,180 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (354 hom., cov: 32)
  • Exomes 𝑓: 0.012 (137 hom.)
• Consequence: ORC1 NM_004153.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.146

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-52372950-G-A is Benign according to our data. Variant chr1-52372950-G-A is described in ClinVar as [Benign]. Clinvar id is 297574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC1	NM_004153.4	c.*231C>T		3_prime_UTR_variant	17/17	ENST00000371568.8	NP_004144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC1	ENST00000371568.8	c.*231C>T		3_prime_UTR_variant	17/17	1	NM_004153.4	ENSP00000360623	P1
ORC1	ENST00000371566.1	c.*231C>T		3_prime_UTR_variant	17/17	1		ENSP00000360621	P1

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 6243 AN: 152120 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00845

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.0125 AC: 4783 AN: 382942 Hom.: 137 Cov.: 2 AF XY: 0.0128 AC XY: 2612 AN XY: 204690

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.00845

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.00407

Gnomad4 NFE exome AF: 0.00818

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0412 AC: 6270 AN: 152238 Hom.: 354 Cov.: 32 AF XY: 0.0408 AC XY: 3038 AN XY: 74420

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.00844

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0210 Hom.: 52

Bravo AF: 0.0439

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Meier-Gorlin syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs3087471; hg19: chr1-52838622;