chr16-46689707-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PVS1_ModeratePM2PP5BS1_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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:1

Conservation

PhyloP100: 1.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 57 CDS bases. Genomic position: 46689762. Lost 0.075 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

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 id is 253272.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}. Variant chr16-46689707-T-C is described in Lovd as [Likely_pathogenic].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORC6	NM_014321.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000219097.7	NP_055136.1	Q9Y5N6A0A024R6R3
ORC6	XM_011522978.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 6		XP_011521280.1
ORC6	NR_037620.2 link	n.49T>C		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC6	ENST00000219097.7 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	1	NM_014321.4	ENSP00000219097.2		Q9Y5N6

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000283

AC:

AN:

222746

Hom.:

AF XY:

0.000223

AC XY:

AN XY:

121052

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000573

AC XY:

412

AN XY:

719430

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000185

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.000742

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.000348

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000494

Hom.:

Bravo

AF:

0.000385

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000183

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Uncertain:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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

- -

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

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‚ÄìGorlin 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. -

Meier-Gorlin syndrome 3

Pathogenic:5

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. -

Aug 30, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

May 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Benign

0.58

DEOGEN2

Benign

0.053

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Benign

-0.79

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0050

B;.

Vest4

0.80

MVP

0.81

ClinPred

0.86

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.93

gMVP

0.61

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