rs144065502

Variant names:

• chr16-46689659-G-A
• rs144065502
• NM_014321.4:c.-47G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-46689659-G-A
• chr16-46689659-G-C
• chr16-46689659-G-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014321.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	NM_014321.4	MANE Select	c.-47G>A		5_prime_UTR	Exon 1 of 7	NP_055136.1
	ORC6	NR_037620.2		n.1G>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	ENST00000219097.7	TSL:1 MANE Select	c.-47G>A		5_prime_UTR	Exon 1 of 7	ENSP00000219097.2
	ORC6	ENST00000912416.1		c.-47G>A		5_prime_UTR	Exon 1 of 7	ENSP00000582475.1
	ORC6	ENST00000912417.1		c.-47G>A		5_prime_UTR	Exon 1 of 7	ENSP00000582476.1

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

GnomAD2 exomes AF: 0.00515 AC: 928 AN: 180134 AF XY: 0.00543

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.: 28 Cov.: 30 AF XY: 0.00387 AC XY: 2715 AN XY: 702282

African (AFR) AF: 0.000881 AC: 29 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: 0 AN: 38052

South Asian (SAS) AF: 0.00719 AC: 586 AN: 81484

European-Finnish (FIN) AF: 0.000245 AC: 12 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

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

African (AFR) AF: 0.000409 AC: 17 AN: 41580

American (AMR) AF: 0.00424 AC: 65 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10630

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68034

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00560 Hom.: 2

Bravo AF: 0.00368

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Meier-Gorlin syndrome (1)
-	-	1	Meier-Gorlin syndrome 3 (1)
-	-	1	not specified (1)
-	-	1	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		1.8
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs144065502; hg19: chr16-46723571;