rs144065502

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000219097.7(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
ENST00000219097.7 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.81

Variant links:

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]

ORC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
ORC6	NM_014321.4 linkuse as main transcript	c.-47G>A	5_prime_UTR_variant	1/7	ENST00000219097.7	NP_055136.1
ORC6	XM_011522978.4 linkuse as main transcript	c.-47G>A	5_prime_UTR_variant	1/6		XP_011521280.1
ORC6	NR_037620.2 linkuse as main transcript	n.1G>A	non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC6	ENST00000219097.7 linkuse as main transcript	c.-47G>A		5_prime_UTR_variant	1/7	1	NM_014321.4	ENSP00000219097	P1

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

522

AN:

152234

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00543

AC XY:

528

AN XY:

97182

show subpopulations

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.:

Cov.:

AF XY:

0.00387

AC XY:

2715

AN XY:

702282

show subpopulations

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.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74496

show subpopulations

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.:

Bravo

AF:

0.00368

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over