chr16-46689707-T-C

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

5
4
7

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]

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
ORC6NM_014321.4 linkc.2T>C p.Met1? start_lost Exon 1 of 7 ENST00000219097.7 NP_055136.1 Q9Y5N6A0A024R6R3
ORC6XM_011522978.4 linkc.2T>C p.Met1? start_lost Exon 1 of 6 XP_011521280.1
ORC6NR_037620.2 linkn.49T>C non_coding_transcript_exon_variant Exon 1 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ORC6ENST00000219097.7 linkc.2T>C p.Met1? start_lost Exon 1 of 7 1 NM_014321.4 ENSP00000219097.2 Q9Y5N6

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
152038
Hom.:
0
Cov.:
33
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:
63
AN:
222746
Hom.:
0
AF XY:
0.000223
AC XY:
27
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.:
0
Cov.:
33
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:
53
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.000309
AC XY:
23
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.:
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: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–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. -

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
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
24
DANN
Benign
0.58
DEOGEN2
Benign
0.053
T;T
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.031
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Uncertain
0.54
D;D
MetaSVM
Benign
-0.79
T
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
D
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.

Other links and lift over

dbSNP: rs146795505; hg19: chr16-46723619; API