chr2-147938178-C-T

Position:

chr2-147938178-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_181741.4(ORC4):c.1090G>A(p.Val364Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,612,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 1 hom. )

Consequence

ORC4
NM_181741.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.11

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008985847).

BP6

Variant 2-147938178-C-T is Benign according to our data. Variant chr2-147938178-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436116.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00133 (203/152142) while in subpopulation AFR AF= 0.00318 (132/41514). AF 95% confidence interval is 0.00274. There are 0 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC4	NM_181741.4 linkuse as main transcript	c.1090G>A	p.Val364Ile	missense_variant	13/14	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.1090G>A	p.Val364Ile	missense_variant	13/14	1	NM_181741.4	ENSP00000376597	P1	O43929-1

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

203

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000659

AC:

165

AN:

250442

Hom.:

AF XY:

0.000569

AC XY:

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.00353

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000725

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000807

AC:

1178

AN:

1460290

Hom.:

Cov.:

AF XY:

0.000776

AC XY:

564

AN XY:

726530

show subpopulations

Gnomad4 AFR exome

AF:

0.00398

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000863

Gnomad4 OTH exome

AF:

0.000862

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152142

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00318

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000708

Hom.:

Bravo

AF:

0.00181

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000643

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 14, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.1090G>A (p.V364I) alteration is located in exon 13 (coding exon 12) of the ORC4 gene. This alteration results from a G to A substitution at nucleotide position 1090, causing the valine (V) at amino acid position 364 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

- -

ORC4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.0058

.;T;.;T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.085

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.79

T;T;T;.;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.0090

T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.93

.;L;.;L;L

MutationTaster

Benign

0.87

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

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.040

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.46

T;T;T;T;T

Sift4G

Benign

0.75

T;T;T;T;T

Polyphen

0.0010

.;B;.;B;B

Vest4

0.10

MVP

0.67

MPC

0.076

ClinPred

0.012

GERP RS

5.0

Varity_R

0.13

gMVP

0.14

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