rs33994299

chr16-46689686-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014321.4(ORC6):c.-20T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,592,648 control chromosomes in the GnomAD database, including 157,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10752 hom., cov: 33)
  • Exomes 𝑓: 0.44 (147189 hom.)
• Consequence: ORC6 NM_014321.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.22

Genes affected

ORC6 (HGNC:17151): (origin recognition complex subunit 6) 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. The protein encoded by this gene is a subunit of the ORC complex. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-46689686-T-C is Benign according to our data. Variant chr16-46689686-T-C is described in ClinVar as [Benign]. Clinvar id is 260386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-46689686-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC6	NM_014321.4	c.-20T>C		5_prime_UTR_variant	1/7	ENST00000219097.7
ORC6	XM_011522978.4	c.-20T>C		5_prime_UTR_variant	1/6
ORC6	NR_037620.2	n.28T>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC6	ENST00000219097.7	c.-20T>C		5_prime_UTR_variant	1/7	1	NM_014321.4	P1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50759 AN: 151980 Hom.: 10755 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.375

GnomAD3 exomes AF: 0.342 AC: 72526 AN: 211814 Hom.: 14807 AF XY: 0.352 AC XY: 40438 AN XY: 114780

Gnomad AFR exome AF: 0.0910

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.0393

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.438 AC: 631076 AN: 1440550 Hom.: 147189 Cov.: 41 AF XY: 0.434 AC XY: 310249 AN XY: 714584

Gnomad4 AFR exome AF: 0.0937

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.445

Gnomad4 EAS exome AF: 0.0414

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.419

Gnomad4 NFE exome AF: 0.484

Gnomad4 OTH exome AF: 0.415

GnomAD4 genome AF: 0.334 AC: 50759 AN: 152098 Hom.: 10752 Cov.: 33 AF XY: 0.329 AC XY: 24495 AN XY: 74348

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.0419

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.477

Gnomad4 OTH AF: 0.370

Alfa AF: 0.445 Hom.: 25495

Bravo AF: 0.318

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meier-Gorlin syndrome 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Meier-Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Parkinson Disease, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.7
Dann	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs33994299; hg19: chr16-46723598; COSMIC: COSV54478220; COSMIC: COSV54478220;