rs1164764682

Variant names:

• chr16-46691017-C-T
• rs1164764682
• NM_014321.4:c.92C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014321.4(ORC6):​c.92C>T​(p.Ser31Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ORC6 NM_014321.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.81
• Publications: 0 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]

ORC6 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	NM_014321.4	MANE Select	c.92C>T	p.Ser31Phe	missense	Exon 2 of 7	NP_055136.1	Q9Y5N6
	ORC6	NR_037620.2		n.198C>T		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	ENST00000219097.7	TSL:1 MANE Select	c.92C>T	p.Ser31Phe	missense	Exon 2 of 7	ENSP00000219097.2	Q9Y5N6
	ORC6	ENST00000912416.1		c.92C>T	p.Ser31Phe	missense	Exon 2 of 7	ENSP00000582475.1
	ORC6	ENST00000912417.1		c.92C>T	p.Ser31Phe	missense	Exon 2 of 7	ENSP00000582476.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.48	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.68		Loss of disorder (P = 0.0107)
MVP		0.84
MPC		0.44
ClinPred		0.93	D
GERP RS		5.2
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.66
Mutation Taster		=244/56	polymorphism

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: rs1164764682; hg19: chr16-46724929;