dbSNP rs750064136: ORC5:p.Arg104Leu (chr7-104200813-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002553.4(ORC5):c.311G>T(p.Arg104Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R104H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ORC5
NM_002553.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.72

Publications

0 publications found

Variant links:

Genes affected

ORC5 (HGNC:8491): (origin recognition complex subunit 5) 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. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Oct 2010]

ORC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002553.4. 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
	ORC5	NM_002553.4	MANE Select	c.311G>T	p.Arg104Leu	missense	Exon 3 of 14	NP_002544.1	O43913-1
	ORC5	NM_181747.4		c.311G>T	p.Arg104Leu	missense	Exon 3 of 9	NP_859531.1	O43913-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC5	ENST00000297431.9	TSL:1 MANE Select	c.311G>T	p.Arg104Leu	missense	Exon 3 of 14	ENSP00000297431.4	O43913-1
ORC5	ENST00000447452.6	TSL:1	c.311G>T	p.Arg104Leu	missense	Exon 3 of 9	ENSP00000395747.2	O43913-2
ORC5	ENST00000938620.1		c.311G>T	p.Arg104Leu	missense	Exon 3 of 15	ENSP00000608679.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110600

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.56

MutationAssessor

Benign

2.0

PhyloP100

2.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.33

Sift

Uncertain

0.026

Sift4G

Benign

0.23

Polyphen

0.93

Vest4

0.81

MutPred

0.51

Gain of ubiquitination at K107 (P = 0.0441)

MVP

0.83

MPC

0.19

ClinPred

0.97

GERP RS

4.8

Varity_R

0.76

gMVP

0.62

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over