NM_181741.4:c.353T>C

Variant names:

• chr2-147958332-A-G
• rs61750441
• NM_181741.4:c.353T>C
• ORC4 p.Leu118Ser

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The NM_181741.4(ORC4):​c.353T>C​(p.Leu118Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,612,158 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 8.83
• Publications: 8 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 -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.14341849).
• BP6: Variant 2-147958332-A-G is Benign according to our data. Variant chr2-147958332-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211806.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00143 (218/152196) while in subpopulation NFE AF = 0.00233 (158/67940). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

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.353T>C	p.Leu118Ser	missense	Exon 6 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.353T>C	p.Leu118Ser	missense	Exon 7 of 15	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.353T>C	p.Leu118Ser	missense	Exon 8 of 16	NP_001361199.1	O43929-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.353T>C	p.Leu118Ser	missense	Exon 6 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.353T>C	p.Leu118Ser	missense	Exon 6 of 15	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.353T>C	p.Leu118Ser	missense	Exon 6 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00233

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00161 AC: 403 AN: 250922 AF XY: 0.00168

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00255 AC: 3727 AN: 1459962 Hom.: 9 Cov.: 29 AF XY: 0.00251 AC XY: 1820 AN XY: 726348

African (AFR) AF: 0.000359 AC: 12 AN: 33424

American (AMR) AF: 0.00112 AC: 50 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86134

European-Finnish (FIN) AF: 0.000544 AC: 29 AN: 53348

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5752

European-Non Finnish (NFE) AF: 0.00299 AC: 3319 AN: 1110672

Other (OTH) AF: 0.00254 AC: 153 AN: 60302

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74404

African (AFR) AF: 0.000649 AC: 27 AN: 41580

American (AMR) AF: 0.00151 AC: 23 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00233 AC: 158 AN: 67940

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00166

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00317

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	not specified (1)
-	-	1	ORC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		8.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.87
Mutation Taster		=82/18	polymorphism

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

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

Other links and lift over

dbSNP: rs61750441;

hg19: chr2-148715901;

COSMIC: COSV99068414;

COSMIC: COSV99068414;