16-46689686-T-C

Variant names:

• chr16-46689686-T-C
• rs33994299
• NM_014321.4:c.-20T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.22
• Publications: 21 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 -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 VariationId is 260386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

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.-20T>C		5_prime_UTR	Exon 1 of 7	NP_055136.1
	ORC6	NR_037620.2		n.28T>C		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.-20T>C		5_prime_UTR	Exon 1 of 7	ENSP00000219097.2
	ORC6	ENST00000912416.1		c.-20T>C		5_prime_UTR	Exon 1 of 7	ENSP00000582475.1
	ORC6	ENST00000912417.1		c.-20T>C		5_prime_UTR	Exon 1 of 7	ENSP00000582476.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50759 AN: 151980 Hom.: 10755 Cov.: 33

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

GnomAD2 exomes AF: 0.342 AC: 72526 AN: 211814 AF XY: 0.352

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 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.: 41 AF XY: 0.434 AC XY: 310249 AN XY: 714584

African (AFR) AF: 0.0937 AC: 3121 AN: 33306

American (AMR) AF: 0.259 AC: 10873 AN: 42018

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 11440 AN: 25688

East Asian (EAS) AF: 0.0414 AC: 1614 AN: 39016

South Asian (SAS) AF: 0.274 AC: 22864 AN: 83584

European-Finnish (FIN) AF: 0.419 AC: 21249 AN: 50774

Middle Eastern (MID) AF: 0.410 AC: 2350 AN: 5736

European-Non Finnish (NFE) AF: 0.484 AC: 532907 AN: 1100978

Other (OTH) AF: 0.415 AC: 24658 AN: 59450

GnomAD4 genome AF: 0.334 AC: 50759 AN: 152098 Hom.: 10752 Cov.: 33 AF XY: 0.329 AC XY: 24495 AN XY: 74348

African (AFR) AF: 0.103 AC: 4283 AN: 41546

American (AMR) AF: 0.353 AC: 5392 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1556 AN: 3468

East Asian (EAS) AF: 0.0419 AC: 215 AN: 5134

South Asian (SAS) AF: 0.247 AC: 1192 AN: 4826

European-Finnish (FIN) AF: 0.401 AC: 4247 AN: 10584

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32422 AN: 67934

Other (OTH) AF: 0.370 AC: 782 AN: 2112

Alfa AF: 0.435 Hom.: 36362

Bravo AF: 0.318

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Meier-Gorlin syndrome 3 (2)
-	-	1	Meier-Gorlin syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.34
PhyloP100		-1.2
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs33994299; hg19: chr16-46723598; COSMIC: COSV54478220; COSMIC: COSV54478220;