rs144065502

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.81

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Parkinson disease 17
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

VPS35 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 260387.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ORC6	NM_014321.4 link	c.-47G>A	5_prime_UTR_variant	Exon 1 of 7	ENST00000219097.7	NP_055136.1	Q9Y5N6A0A024R6R3
ORC6	NR_037620.2 link	n.1G>A	non_coding_transcript_exon_variant	Exon 1 of 7
ORC6	XM_011522978.4 link	c.-47G>A	5_prime_UTR_variant	Exon 1 of 6		XP_011521280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC6	ENST00000219097.7 link	c.-47G>A		5_prime_UTR_variant	Exon 1 of 7	1	NM_014321.4	ENSP00000219097.2		Q9Y5N6

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

GnomAD2 exomes

AF:

0.00515

AC:

928

AN:

180134

AF XY:

0.00543

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 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

African (AFR)

AF:

0.000881

AC:

AN:

32918

American (AMR)

AF:

0.00384

AC:

148

AN:

38552

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

804

AN:

25358

East Asian (EAS)

AF:

0.00

AC:

AN:

38052

South Asian (SAS)

AF:

0.00719

AC:

586

AN:

81484

European-Finnish (FIN)

AF:

0.000245

AC:

AN:

48996

Middle Eastern (MID)

AF:

0.0318

AC:

182

AN:

5722

European-Non Finnish (NFE)

AF:

0.00276

AC:

3009

AN:

1089960

Other (OTH)

AF:

0.00637

AC:

374

AN:

58686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

272

544

815

1087

1359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00343

AC:

523

AN:

152352

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41580

American (AMR)

AF:

0.00424

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0285

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00683

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00372

AC:

253

AN:

68034

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00560

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meier-Gorlin syndrome 3

Benign:1

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. -

Parkinson Disease, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely 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

-0.71

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.8

PromoterAI

-0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over