16-46689707-T-C

Variant names:

• chr16-46689707-T-C
• rs146795505
• NM_014321.4:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PVS1_Moderate PP5 BS1_Supporting

The NM_014321.4(ORC6):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,600,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: ORC6 NM_014321.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: 1.86
• Publications: 15 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: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 20 codons. Genomic position: 46689763. Lost 0.076 part of the original CDS.
• PP5: Variant 16-46689707-T-C is Pathogenic according to our data. Variant chr16-46689707-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 253272.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000348 (53/152156) while in subpopulation NFE AF = 0.000662 (45/67980). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	NM_014321.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	NP_055136.1
	ORC6	NR_037620.2		n.49T>C		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	ENST00000219097.7	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENSP00000219097.2
	ORC6	ENST00000568364.6	TSL:5	c.2T>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000457282.2
	ORC6	ENST00000563306.5	TSL:2	n.26T>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152038 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000283 AC: 63 AN: 222746 AF XY: 0.000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.000590 AC: 855 AN: 1448794 Hom.: 0 Cov.: 33 AF XY: 0.000573 AC XY: 412 AN XY: 719430

African (AFR) AF: 0.0000899 AC: 3 AN: 33380

American (AMR) AF: 0.000185 AC: 8 AN: 43178

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 84348

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51392

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.000742 AC: 821 AN: 1105854

Other (OTH) AF: 0.000335 AC: 20 AN: 59754

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74412

African (AFR) AF: 0.0000722 AC: 3 AN: 41524

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000575 Hom.: 0

Bravo AF: 0.000385

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000183 AC: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:6 Uncertain:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 34426522, 31589614, 36012502, 22333897)

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the ORC6 mRNA. The next in-frame methionine is located at codon 20. This variant is present in population databases (rs146795505, gnomAD 0.06%). Disruption of the initiator codon has been observed in individual(s) with Meier–Gorlin syndrome (PMID: 22333897, 36012502). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 253272). For these reasons, this variant has been classified as Pathogenic.

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Meier-Gorlin syndrome 3 Pathogenic:6

Sep 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Aug 30, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ORC6 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 222746 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ORC6 causing Meier-Gorlin Syndrome 3, allowing no conclusion about variant significance. c.2T>C has been reported in the literature in compound heterozygous individuals affected with Meier-Gorlin Syndrome 3 (de Munnik_2012, Nazarenko_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36012502, 22333897). ClinVar contains an entry for this variant (Variation ID: 253272). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jan 12, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ORC6 c.2T>C (p.Met1?) variant is a stop-lost variant that is predicted to result in an elongation of the protein. This variant has been reported in one study and is found in a compound heterozygous state in four individuals from three families with Meier-Gorlin syndrome (De Munnik et al. 2012). The p.Met1? variant is reported at a frequency of 0.000601 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Met1? variant is classified likely pathogenic for Meier-Gorlin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Apr 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ORC6 c.2T>C; p.Met1? variant (rs146795505, ClinVar Variation ID: 253272) is reported in the literature in at least four probands affected with Meier-Gorlin syndrome, all of whom carried the c.449+5G>A variant in trans (de Munnik 2012, Nazarenko 2022). This variant is found in the general population with an overall allele frequency of 0.03% (75/254,098 alleles) in the Genome Aggregation Database (v2.1.1). This variant abolishes the canonical translation initiation site, which is likely to disrupt gene function; however, it is not known if downstream in-frame initiation sites could be used. Based on available information, this variant is considered to be likely pathogenic. References: de Munnik SA et al. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. Eur J Hum Genet. 2012 Jun;20(6):598-606. PMID: 22333897. Nazarenko MS et al. Meier-Gorlin Syndrome: Clinical Misdiagnosis, Genetic Testing and Functional Analysis of ORC6 Mutations and the Development of a Prenatal Test. Int J Mol Sci. 2022 Aug 17;23(16):9234. PMID: 36012502.

ORC6-related disorder Pathogenic:1

Mar 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ORC6 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). This variant along with another ORC6 splicing variant has been reported in four patients from three families with autosomal recessive Meier-Gorlin syndrome (de Munnik. 2012. PubMed ID: 22333897, see table 2). This variant in the heterozygous condition was reported in another patient with autosomal recessive Meier-Gorlin syndrome, a second plausible causative ORC6 variant was not described (Reuter et al. 2018. PubMed ID: 29431110, see appendix table S1).This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Benign	0.58
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.79	T
PhyloP100		1.9
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0050	B
Vest4		0.80
MVP		0.81
ClinPred		0.86	D
GERP RS		4.9
PromoterAI		-0.33	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.61
Mutation Taster		=11/189	disease causing (ClinVar)

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: rs146795505; hg19: chr16-46723619;