16-46689707-T-C

Position:

chr16-46689707-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PVS1PS1_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:8U: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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_014321.4 (ORC6) was described as [Pathogenic] in ClinVar as 436124

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: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}. Variant chr16-46689707-T-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00059 (855/1448794) while in subpopulation NFE AF= 0.000742 (821/1105854). AF 95% confidence interval is 0.0007. There are 0 homozygotes in gnomad4_exome. There are 412 alleles in male gnomad4_exome 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/exons	MANE
ORC6	NM_014321.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/7	ENST00000219097.7
ORC6	XM_011522978.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/6
ORC6	NR_037620.2 linkuse as main transcript	n.49T>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC6	ENST00000219097.7 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/7	1	NM_014321.4	P1

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:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	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 individuals with Meier‚ÄìGorlin syndrome (PMID: 22333897). ClinVar contains an entry for this variant (Variation ID: 253272). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2023	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) -

Meier-Gorlin syndrome 3

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 05, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2019	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. -

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

MutationTaster

Benign

1.0

D;D

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