rs2307394

Variant names:

• chr2-147958859-T-C
• rs2307394
• NM_181741.4:c.233A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-147958859-T-C
• chr2-147958859-T-A
• chr2-147958859-T-G

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.233A>G​(p.Asn78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,254,158 control chromosomes in the GnomAD database, including 64,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8278 hom., cov: 32)
  • Exomes 𝑓: 0.31 (56061 hom.)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.94
• Publications: 79 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=0.0019708276).
• BP6: Variant 2-147958859-T-C is Benign according to our data. Variant chr2-147958859-T-C is described in ClinVar as Benign. ClinVar VariationId is 159483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 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.233A>G	p.Asn78Ser	missense	Exon 5 of 14	NP_859525.1	O43929-1
	ORC4	NM_001190879.3		c.233A>G	p.Asn78Ser	missense	Exon 6 of 15	NP_001177808.1	O43929-1
	ORC4	NM_001374270.1		c.233A>G	p.Asn78Ser	missense	Exon 7 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.233A>G	p.Asn78Ser	missense	Exon 5 of 14	ENSP00000376597.5	O43929-1
	ORC4	ENST00000877934.1		c.233A>G	p.Asn78Ser	missense	Exon 5 of 15	ENSP00000547993.1
	ORC4	ENST00000264169.6	TSL:5	c.233A>G	p.Asn78Ser	missense	Exon 5 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49342 AN: 151556 Hom.: 8273 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.357 AC: 85198 AN: 238644 AF XY: 0.351

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.530

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.313 AC: 345400 AN: 1102484 Hom.: 56061 Cov.: 16 AF XY: 0.313 AC XY: 176816 AN XY: 564144

African (AFR) AF: 0.292 AC: 7704 AN: 26418

American (AMR) AF: 0.453 AC: 19744 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8030 AN: 23744

East Asian (EAS) AF: 0.504 AC: 18890 AN: 37472

South Asian (SAS) AF: 0.319 AC: 24534 AN: 77008

European-Finnish (FIN) AF: 0.335 AC: 17647 AN: 52620

Middle Eastern (MID) AF: 0.429 AC: 2122 AN: 4948

European-Non Finnish (NFE) AF: 0.293 AC: 231398 AN: 788450

Other (OTH) AF: 0.318 AC: 15331 AN: 48222

GnomAD4 genome AF: 0.326 AC: 49390 AN: 151674 Hom.: 8278 Cov.: 32 AF XY: 0.327 AC XY: 24269 AN XY: 74128

African (AFR) AF: 0.298 AC: 12354 AN: 41408

American (AMR) AF: 0.382 AC: 5819 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3468

East Asian (EAS) AF: 0.513 AC: 2655 AN: 5174

South Asian (SAS) AF: 0.319 AC: 1535 AN: 4818

European-Finnish (FIN) AF: 0.333 AC: 3501 AN: 10498

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21288 AN: 67756

Other (OTH) AF: 0.347 AC: 731 AN: 2104

Alfa AF: 0.322 Hom.: 38169

Bravo AF: 0.333

TwinsUK AF: 0.304 AC: 1128

ALSPAC AF: 0.299 AC: 1153

ESP6500AA AF: 0.309 AC: 1354

ESP6500EA AF: 0.313 AC: 2678

ExAC AF: 0.345 AC: 41728

Asia WGS AF: 0.354 AC: 1223 AN: 3450

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Meier-Gorlin syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.040
Sift	Benign	0.091	T
Sift4G	Benign	0.27	T
Polyphen		0.021	B
Vest4		0.25
MPC		0.074
ClinPred		0.0086	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.24
Mutation Taster		=294/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs2307394; hg19: chr2-148716428; COSMIC: COSV51573412; COSMIC: COSV51573412;