16-46689686-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.22

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:

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

VPS35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	Exon rank	MANE	Protein	UniProt
ORC6	NM_014321.4 link	c.-20T>C	5_prime_UTR_variant	Exon 1 of 7	ENST00000219097.7	NP_055136.1	Q9Y5N6A0A024R6R3
ORC6	XM_011522978.4 link	c.-20T>C	5_prime_UTR_variant	Exon 1 of 6		XP_011521280.1
ORC6	NR_037620.2 link	n.28T>C	non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC6	ENST00000219097 link	c.-20T>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_014321.4	ENSP00000219097.2		Q9Y5N6

Frequencies

GnomAD3 genomes

AF:

0.334

AC:

50759

AN:

151980

Hom.:

10755

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.434

AC XY:

310249

AN XY:

714584

show subpopulations

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.:

AF XY:

0.329

AC XY:

24495

AN XY:

74348

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meier-Gorlin syndrome 3

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meier-Gorlin syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Parkinson Disease, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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