rs3768686

Positions:

• chr2-147935207-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC4	NM_181741.4	c.*303A>G		3_prime_UTR_variant	14/14	ENST00000392857.10	NP_859525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10	c.*303A>G		3_prime_UTR_variant	14/14	1	NM_181741.4	ENSP00000376597	P1

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

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.326

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.439

Gnomad4 FIN exome AF: 0.468

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.354

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

Gnomad4 AFR AF: 0.0871

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.511

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.275

Alfa AF: 0.338 Hom.: 8650

Bravo AF: 0.272

Asia WGS AF: 0.454 AC: 1574 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.38
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs3768686; hg19: chr2-148692776;