rs138876526

chr2-147938178-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.11

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]

ACMG classification

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=2, 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	UniProt
ORC4	NM_181741.4	c.1090G>A	p.Val364Ile	missense_variant	13/14	ENST00000392857.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC4	ENST00000392857.10	c.1090G>A	p.Val364Ile	missense_variant	13/14	1	NM_181741.4	P1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 152024 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000569 AC XY: 77 AN XY: 135416

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.: 1 Cov.: 29 AF XY: 0.000776 AC XY: 564 AN XY: 726530

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.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74390

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.: 0

Bravo AF: 0.00181

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000643 AC: 78

EpiCase AF: 0.000818

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

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

Invitae

Nov 10, 2023

- -

ORC4-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Benign	0.77
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.79	T;T;T;.;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0090	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	0.87	D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
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	T
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

Other links and lift over

dbSNP: rs138876526; hg19: chr2-148695747;