16-46689659-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014321.4(ORC6):c.-47G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,572,080 control chromosomes in the GnomAD database, including 33 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 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (28 hom.)
• Consequence: ORC6 NM_014321.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.81

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-46689659-G-A is Benign according to our data. Variant chr16-46689659-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260387.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00343 (523/152352) while in subpopulation SAS AF= 0.00683 (33/4830). AF 95% confidence interval is 0.005. There are 5 homozygotes in gnomad4. There are 251 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC6	NM_014321.4	c.-47G>A		5_prime_UTR_variant	1/7	ENST00000219097.7
ORC6	XM_011522978.4	c.-47G>A		5_prime_UTR_variant	1/6
ORC6	NR_037620.2	n.1G>A		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC6	ENST00000219097.7	c.-47G>A		5_prime_UTR_variant	1/7	1	NM_014321.4	P1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152234 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00515 AC: 928 AN: 180134 Hom.: 1 AF XY: 0.00543 AC XY: 528 AN XY: 97182

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00767

Gnomad FIN exome AF: 0.000127

Gnomad NFE exome AF: 0.00402

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.00362 AC: 5144 AN: 1419728 Hom.: 28 Cov.: 30 AF XY: 0.00387 AC XY: 2715 AN XY: 702282

Gnomad4 AFR exome AF: 0.000881

Gnomad4 AMR exome AF: 0.00384

Gnomad4 ASJ exome AF: 0.0317

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00719

Gnomad4 FIN exome AF: 0.000245

Gnomad4 NFE exome AF: 0.00276

Gnomad4 OTH exome AF: 0.00637

GnomAD4 genome AF: 0.00343 AC: 523 AN: 152352 Hom.: 5 Cov.: 33 AF XY: 0.00337 AC XY: 251 AN XY: 74496

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00424

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00652 Hom.: 0

Bravo AF: 0.00368

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Meier-Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Meier-Gorlin syndrome 3 Benign:1

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. -

Parkinson Disease, Dominant Benign:1

Likely 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	-0.71
Cadd	Benign	12
Dann	Benign	0.90
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: rs144065502; hg19: chr16-46723571;