16-46689770-G-A

Variant names:

• chr16-46689770-G-A
• rs2143010039
• NM_014321.4:c.65G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014321.4(ORC6):​c.65G>A​(p.Arg22Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ORC6 NM_014321.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.26
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 16-46689770-G-A is Pathogenic according to our data. Variant chr16-46689770-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1173060.Status of the report is criteria_provided_single_submitter, 1 stars.

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.65G>A	p.Arg22Lys	missense splice_region	Exon 1 of 7	NP_055136.1	Q9Y5N6
	ORC6	NR_037620.2		n.112G>A		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	ENST00000219097.7	TSL:1 MANE Select	c.65G>A	p.Arg22Lys	missense splice_region	Exon 1 of 7	ENSP00000219097.2	Q9Y5N6
	ORC6	ENST00000912416.1		c.65G>A	p.Arg22Lys	missense splice_region	Exon 1 of 7	ENSP00000582475.1
	ORC6	ENST00000912417.1		c.65G>A	p.Arg22Lys	missense splice_region	Exon 1 of 7	ENSP00000582476.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meier-Gorlin syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Benign	0.91
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Polyphen		0.57	P
Vest4		0.52
MutPred		0.52		Gain of ubiquitination at R22 (P = 0.017)
MVP		0.50
MPC		0.21
ClinPred		0.91	D
GERP RS		5.8
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.35
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2143010039; hg19: chr16-46723682;