rs200089121
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_014321.4(ORC6):c.235T>A(p.Tyr79Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,810 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
ORC6
NM_014321.4 missense
NM_014321.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 6.64
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.927
PP5
?
Variant 16-46692421-T-A is Pathogenic according to our data. Variant chr16-46692421-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436123.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ORC6 | NM_014321.4 | c.235T>A | p.Tyr79Asn | missense_variant | 3/7 | ENST00000219097.7 | |
ORC6 | XM_011522978.4 | c.235T>A | p.Tyr79Asn | missense_variant | 3/6 | ||
ORC6 | NR_037620.2 | n.341T>A | non_coding_transcript_exon_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ORC6 | ENST00000219097.7 | c.235T>A | p.Tyr79Asn | missense_variant | 3/7 | 1 | NM_014321.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251428Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135904
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461488Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727084
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Meier-Gorlin syndrome 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 28, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | The c.235T>A (p.Y79N) alteration is located in exon 3 (coding exon 3) of the ORC6 gene. This alteration results from a T to A substitution at nucleotide position 235, causing the tyrosine (Y) at amino acid position 79 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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