chr1-52373320-A-G

Position:

chr1-52373320-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC1	NM_004153.4 linkuse as main transcript	c.2447T>C	p.Met816Thr	missense_variant	17/17	ENST00000371568.8	NP_004144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC1	ENST00000371568.8 linkuse as main transcript	c.2447T>C	p.Met816Thr	missense_variant	17/17	1	NM_004153.4	ENSP00000360623	P1
ORC1	ENST00000371566.1 linkuse as main transcript	c.2447T>C	p.Met816Thr	missense_variant	17/17	1		ENSP00000360621	P1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2573

AN:

152214

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0188

AC XY:

2561

AN XY:

135902

show subpopulations

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.:

AF XY:

0.0217

AC XY:

15749

AN XY:

727220

show subpopulations

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.:

Cov.:

AF XY:

0.0164

AC XY:

1222

AN XY:

74484

show subpopulations

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.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0247

AC:

212

ExAC

AF:

0.0205

AC:

2486

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0238

EpiControl

AF:

0.0251

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.012

T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.033

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.43

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over