NM_181741.4:c.166C>G

Variant names:

• chr2-147972798-G-C
• rs2307397
• NM_181741.4:c.166C>G
• ORC4 p.Leu56Val

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181741.4(ORC4):​c.166C>G​(p.Leu56Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,610,564 control chromosomes in the GnomAD database, including 1,929 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L56F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.034 (121 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1808 hom.)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.152
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019108951).
• BP6: Variant 2-147972798-G-C is Benign according to our data. Variant chr2-147972798-G-C is described in ClinVar as Benign. ClinVar VariationId is 159482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181741.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	NM_181741.4	MANE Select	c.166C>G	p.Leu56Val	missense	Exon 4 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190882.3		c.-57C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001177811.1	O43929-3
	ORC4	NM_001374272.1		c.-152C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001361201.1	O43929-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.166C>G	p.Leu56Val	missense	Exon 4 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000540442.5	TSL:2	c.-57C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	ENSP00000438326.1	O43929-3
	ORC4	ENST00000877934.1		c.166C>G	p.Leu56Val	missense	Exon 4 of 15	ENSP00000547993.1

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5183 AN: 152030 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.00971

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0368

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.0513

GnomAD2 exomes AF: 0.0370 AC: 9278 AN: 250956 AF XY: 0.0377

Gnomad AFR exome AF: 0.00979

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0545

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0538

Gnomad OTH exome AF: 0.0439

GnomAD4 exome AF: 0.0466 AC: 68011 AN: 1458416 Hom.: 1808 Cov.: 29 AF XY: 0.0464 AC XY: 33666 AN XY: 725680

African (AFR) AF: 0.00922 AC: 308 AN: 33414

American (AMR) AF: 0.0290 AC: 1297 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 1436 AN: 26078

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39640

South Asian (SAS) AF: 0.0269 AC: 2321 AN: 86178

European-Finnish (FIN) AF: 0.0207 AC: 1102 AN: 53362

Middle Eastern (MID) AF: 0.0599 AC: 345 AN: 5762

European-Non Finnish (NFE) AF: 0.0526 AC: 58357 AN: 1109058

Other (OTH) AF: 0.0471 AC: 2839 AN: 60266

GnomAD4 genome AF: 0.0341 AC: 5184 AN: 152148 Hom.: 121 Cov.: 32 AF XY: 0.0325 AC XY: 2414 AN XY: 74378

African (AFR) AF: 0.00968 AC: 402 AN: 41538

American (AMR) AF: 0.0368 AC: 562 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 190 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4818

European-Finnish (FIN) AF: 0.0189 AC: 200 AN: 10574

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0523 AC: 3552 AN: 67970

Other (OTH) AF: 0.0508 AC: 107 AN: 2108

Alfa AF: 0.0498 Hom.: 155

Bravo AF: 0.0358

Asia WGS AF: 0.0170 AC: 61 AN: 3472

EpiCase AF: 0.0561

EpiControl AF: 0.0571

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.6
DANN	Benign	0.94
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.15
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.13
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.17
Mutation Taster		=293/7	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2307397;

hg19: chr2-148730367;

COSMIC: COSV51573432;