NM_014321.4:c.71C>T

Variant names:

• chr16-46690996-C-T
• rs1279789023
• NM_014321.4:c.71C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_014321.4(ORC6):​c.71C>T​(p.Ala24Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,848 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: 0.0000014 (0 hom.)
• Consequence: ORC6 NM_014321.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.48
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 16-46690996-C-T is Pathogenic according to our data. Variant chr16-46690996-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1173059.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.71C>T	p.Ala24Val	missense	Exon 2 of 7	NP_055136.1	Q9Y5N6
	ORC6	NR_037620.2		n.177C>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.71C>T	p.Ala24Val	missense	Exon 2 of 7	ENSP00000219097.2	Q9Y5N6
	ORC6	ENST00000912416.1		c.71C>T	p.Ala24Val	missense	Exon 2 of 7	ENSP00000582475.1
	ORC6	ENST00000912417.1		c.71C>T	p.Ala24Val	missense	Exon 2 of 7	ENSP00000582476.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251486 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 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: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.84		Gain of methylation at K23 (P = 0.043)
MVP		0.81
MPC		0.44
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.68
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1279789023; hg19: chr16-46724908;