chr6-87603511-C-T

Position:

• chr6-87603511-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001197259.2(ORC3):​c.-125C>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ORC3 NM_001197259.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

Genes affected

ORC3 (HGNC:8489): (origin recognition complex subunit 3) The origin recognition complex (ORC) is a highly conserved six subunits 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. Studies of a similar gene in Drosophila suggested a possible role of this protein in neuronal proliferation and olfactory memory. Alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene. [provided by RefSeq, Jul 2008]

ORC3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC3	NM_012381.4	c.305C>T	p.Thr102Ile	missense_variant	4/20	ENST00000392844.8	NP_036513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC3	ENST00000392844.8	c.305C>T	p.Thr102Ile	missense_variant	4/20	1	NM_012381.4	ENSP00000376586.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.305C>T (p.T102I) alteration is located in exon 4 (coding exon 4) of the ORC3 gene. This alteration results from a C to T substitution at nucleotide position 305, causing the threonine (T) at amino acid position 102 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.83	P;P
Vest4		0.83
MutPred		0.86		Gain of catalytic residue at L107 (P = 0.0306);Gain of catalytic residue at L107 (P = 0.0306);
MVP		0.49
MPC		0.51
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.51
gMVP		0.80

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: rs1778119991; hg19: chr6-88313229;