NM_181741.4:c.*303A>G

Variant names:

• chr2-147935207-T-C
• rs3768686
• NM_181741.4:c.*303A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181741.4(ORC4):​c.*303A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 315,970 control chromosomes in the GnomAD database, including 20,264 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (8436 hom., cov: 32)
  • Exomes 𝑓: 0.36 (11828 hom.)
• Consequence: ORC4 NM_181741.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 12 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.459 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	NM_181741.4	MANE Select	c.*303A>G		3_prime_UTR	Exon 14 of 14	NP_859525.1
	ORC4	NM_001190879.3		c.*303A>G		3_prime_UTR	Exon 15 of 15	NP_001177808.1
	ORC4	NM_001374270.1		c.*303A>G		3_prime_UTR	Exon 16 of 16	NP_001361199.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC4	ENST00000392857.10	TSL:1 MANE Select	c.*303A>G		3_prime_UTR	Exon 14 of 14	ENSP00000376597.5
	ORC4	ENST00000264169.6	TSL:5	c.*303A>G		3_prime_UTR	Exon 14 of 14	ENSP00000264169.2
	ORC4	ENST00000535373.5	TSL:5	c.*303A>G		3_prime_UTR	Exon 15 of 15	ENSP00000441953.1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45653 AN: 151888 Hom.: 8426 Cov.: 32

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.361 AC: 59222 AN: 163964 Hom.: 11828 Cov.: 0 AF XY: 0.370 AC XY: 31884 AN XY: 86276

African (AFR) AF: 0.0813 AC: 443 AN: 5448

American (AMR) AF: 0.326 AC: 2146 AN: 6578

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 1076 AN: 4942

East Asian (EAS) AF: 0.373 AC: 3453 AN: 9266

South Asian (SAS) AF: 0.439 AC: 9065 AN: 20630

European-Finnish (FIN) AF: 0.468 AC: 3560 AN: 7606

Middle Eastern (MID) AF: 0.176 AC: 120 AN: 680

European-Non Finnish (NFE) AF: 0.362 AC: 36076 AN: 99544

Other (OTH) AF: 0.354 AC: 3283 AN: 9270

GnomAD4 genome AF: 0.301 AC: 45680 AN: 152006 Hom.: 8436 Cov.: 32 AF XY: 0.312 AC XY: 23188 AN XY: 74274

African (AFR) AF: 0.0871 AC: 3616 AN: 41514

American (AMR) AF: 0.340 AC: 5182 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3466

East Asian (EAS) AF: 0.378 AC: 1951 AN: 5156

South Asian (SAS) AF: 0.475 AC: 2287 AN: 4810

European-Finnish (FIN) AF: 0.511 AC: 5395 AN: 10560

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25472 AN: 67942

Other (OTH) AF: 0.275 AC: 579 AN: 2104

Alfa AF: 0.327 Hom.: 10388

Bravo AF: 0.272

Asia WGS AF: 0.454 AC: 1574 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.38
DANN	Benign	0.69
PhyloP100		-1.3
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs3768686; hg19: chr2-148692776;