chr2-147939241-G-A

Position:

chr2-147939241-G-A

Variant summary

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

The ENST00000392857.10(ORC4):c.857C>T(p.Ala286Val) variant causes a missense change. The variant allele was found at a frequency of 0.00437 in 1,606,638 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 23 hom. )

Consequence

ORC4
ENST00000392857.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.49

Variant links:

Genes affected

ORC4 (HGNC:8490): (origin recognition complex subunit 4) The origin recognition complex (ORC) is a highly conserved six subunit 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. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]

ORC4 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=0.013050824).

BP6

Variant 2-147939241-G-A is Benign according to our data. Variant chr2-147939241-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00302 (459/152234) while in subpopulation NFE AF= 0.005 (340/68012). AF 95% confidence interval is 0.00456. There are 0 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC4	NM_181741.4 linkuse as main transcript	c.857C>T	p.Ala286Val	missense_variant	11/14	ENST00000392857.10	NP_859525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10 linkuse as main transcript	c.857C>T	p.Ala286Val	missense_variant	11/14	1	NM_181741.4	ENSP00000376597	P1	O43929-1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

459

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00320

AC:

804

AN:

250942

Hom.:

AF XY:

0.00345

AC XY:

468

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00895

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.00509

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00452

AC:

6568

AN:

1454404

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

3269

AN XY:

724008

show subpopulations

Gnomad4 AFR exome

AF:

0.000780

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00864

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00521

Gnomad4 OTH exome

AF:

0.00468

GnomAD4 genome

AF:

0.00302

AC:

459

AN:

152234

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00500

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00491

Hom.:

Bravo

AF:

0.00346

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00315

AC:

382

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00723

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 20010161) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ORC4: BP4, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.018

.;T;.;T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

D;D;D;.;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Uncertain

2.1

.;M;.;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.68

N;N;N;N;N

REVEL

Uncertain

0.42

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.22

.;B;.;B;B

Vest4

0.69

MVP

0.87

MPC

0.11

ClinPred

0.025

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.41

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