rs777153067

chr16-46689706-A-Gchr16-46689706-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_014321.4(ORC6):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000552 in 1,448,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ORC6 NM_014321.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_014321.4 (ORC6) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 253272
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-46689706-A-G is Pathogenic according to our data. Variant chr16-46689706-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 436124.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORC6	NM_014321.4	c.1A>G	p.Met1?	start_lost	1/7	ENST00000219097.7
ORC6	XM_011522978.4	c.1A>G	p.Met1?	start_lost	1/6
ORC6	NR_037620.2	n.48A>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORC6	ENST00000219097.7	c.1A>G	p.Met1?	start_lost	1/7	1	NM_014321.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000901 AC: 2 AN: 222026 Hom.: 0 AF XY: 0.0000166 AC XY: 2 AN XY: 120624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000205

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1448518 Hom.: 0 Cov.: 33 AF XY: 0.00000417 AC XY: 3 AN XY: 719262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000724

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meier-Gorlin syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 24, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Benign	22
Dann	Benign	0.54
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0010	B;.
Vest4		0.88
MutPred		0.95		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.69
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.58

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

Other links and lift over

dbSNP: rs777153067; hg19: chr16-46723618;