chr6-87616408-A-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_012381.4(ORC3):āc.968A>Cā(p.Asn323Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,459,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.00011 ( 0 hom., cov: 32)
Exomes š: 0.0000046 ( 0 hom. )
Consequence
ORC3
NM_012381.4 missense
NM_012381.4 missense
Scores
2
8
7
Clinical Significance
Conservation
PhyloP100: 7.17
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ORC3 | NM_012381.4 | c.968A>C | p.Asn323Thr | missense_variant | 9/20 | ENST00000392844.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ORC3 | ENST00000392844.8 | c.968A>C | p.Asn323Thr | missense_variant | 9/20 | 1 | NM_012381.4 | A1 | |
ORC3 | ENST00000257789.4 | c.968A>C | p.Asn323Thr | missense_variant | 9/20 | 1 | P4 | ||
ORC3 | ENST00000546266.5 | c.539A>C | p.Asn180Thr | missense_variant | 8/19 | 2 | |||
ORC3 | ENST00000681069.1 | n.1001A>C | non_coding_transcript_exon_variant | 9/15 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249372Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134952
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GnomAD4 exome AF: 0.00000459 AC: 6AN: 1307618Hom.: 0 Cov.: 20 AF XY: 0.00000607 AC XY: 4AN XY: 658500
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2022 | The c.968A>C (p.N323T) alteration is located in exon 9 (coding exon 9) of the ORC3 gene. This alteration results from a A to C substitution at nucleotide position 968, causing the asparagine (N) at amino acid position 323 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;T;T
Polyphen
0.98, 0.95
.;D;P
Vest4
MVP
MPC
0.53
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at