chr1-52389289-G-A

Position:

chr1-52389289-G-A

Variant summary

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

The NM_004153.4(ORC1):c.1115C>T(p.Ala372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,613,960 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 21 hom., cov: 32)

Exomes 𝑓: 0.017 ( 229 hom. )

Consequence

ORC1
NM_004153.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.46

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033430457).

BP6

Variant 1-52389289-G-A is Benign according to our data. Variant chr1-52389289-G-A is described in ClinVar as [Benign]. Clinvar id is 129854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-52389289-G-A is described in Lovd as [Likely_benign]. Variant chr1-52389289-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0136 (2067/152294) while in subpopulation AMR AF= 0.0199 (305/15290). AF 95% confidence interval is 0.0187. There are 21 homozygotes in gnomad4. There are 973 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC1	NM_004153.4 linkuse as main transcript	c.1115C>T	p.Ala372Val	missense_variant	7/17	ENST00000371568.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC1	ENST00000371568.8 linkuse as main transcript	c.1115C>T	p.Ala372Val	missense_variant	7/17	1	NM_004153.4	P1
ORC1	ENST00000371566.1 linkuse as main transcript	c.1115C>T	p.Ala372Val	missense_variant	7/17	1		P1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2064

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00391

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0197

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0267

GnomAD3 exomes

AF:

0.0151

AC:

3797

AN:

251474

Hom.:

AF XY:

0.0150

AC XY:

2037

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0232

Gnomad ASJ exome

AF:

0.0256

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.00966

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0168

AC:

24506

AN:

1461666

Hom.:

229

Cov.:

AF XY:

0.0166

AC XY:

12069

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.0233

Gnomad4 ASJ exome

AF:

0.0246

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00436

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0158

GnomAD4 genome

AF:

0.0136

AC:

2067

AN:

152294

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

973

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00390

Gnomad4 AMR

AF:

0.0199

Gnomad4 ASJ

AF:

0.0259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.0185

Hom.:

Bravo

AF:

0.0149

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0217

AC:

187

ExAC

AF:

0.0149

AC:

1810

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0213

EpiControl

AF:

0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 06, 2015

- -

Meier-Gorlin syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.018

T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.55

.;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.12

Sift

Benign

0.14

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.21

B;B

Vest4

0.062

MPC

0.16

ClinPred

0.0069

GERP RS

3.2

Varity_R

0.021

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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