1-52373320-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004153.4(ORC1):c.2447T>C(p.Met816Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0216 in 1,614,170 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (24 hom., cov: 32)
  • Exomes 𝑓: 0.022 (465 hom.)
• Consequence: ORC1 NM_004153.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.87

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 (MetaRNN=0.0053239763).
• BP6: Variant 1-52373320-A-G is Benign according to our data. Variant chr1-52373320-A-G is described in ClinVar as [Benign]. Clinvar id is 129860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-52373320-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2575/152332) while in subpopulation NFE AF= 0.026 (1771/68032). AF 95% confidence interval is 0.025. There are 24 homozygotes in gnomad4. There are 1222 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC1	NM_004153.4	c.2447T>C	p.Met816Thr	missense_variant	17/17	ENST00000371568.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC1	ENST00000371568.8	c.2447T>C	p.Met816Thr	missense_variant	17/17	1	NM_004153.4	P1
ORC1	ENST00000371566.1	c.2447T>C	p.Met816Thr	missense_variant	17/17	1		P1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2573 AN: 152214 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0190 AC: 4787 AN: 251440 Hom.: 73 AF XY: 0.0188 AC XY: 2561 AN XY: 135902

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00937

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0221 AC: 32289 AN: 1461838 Hom.: 465 Cov.: 31 AF XY: 0.0217 AC XY: 15749 AN XY: 727220

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00917

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.0368

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0169 AC: 2575 AN: 152332 Hom.: 24 Cov.: 32 AF XY: 0.0164 AC XY: 1222 AN XY: 74484

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0227 Hom.: 70

Bravo AF: 0.0151

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0247 AC: 212

ExAC AF: 0.0205 AC: 2486

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0251

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
Dann	Benign	0.74
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.033
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.10
Sift	Benign	0.30	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.025	B;B
Vest4		0.11
MPC		0.18
ClinPred		0.033	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.36

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: rs34521609; hg19: chr1-52838992;