Genetic Variant NM_002553.4:c.898G>C (chr7-104166864-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002553.4(ORC5):c.898G>C(p.Val300Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ORC5
NM_002553.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.78

Publications

3 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20501721).

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.898G>C	p.Val300Leu	missense	Exon 10 of 14	NP_002544.1	O43913-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC5	ENST00000297431.9	TSL:1 MANE Select	c.898G>C	p.Val300Leu	missense	Exon 10 of 14	ENSP00000297431.4	O43913-1
ORC5	ENST00000938620.1		c.991G>C	p.Val331Leu	missense	Exon 11 of 15	ENSP00000608679.1
ORC5	ENST00000884268.1		c.979G>C	p.Val327Leu	missense	Exon 11 of 15	ENSP00000554327.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000798

AC:

AN:

250676

AF XY:

0.0000148

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1454172

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

723882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.00

AC:

AN:

85872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1105438

Other (OTH)

AF:

0.00

AC:

AN:

60172

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.023

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0092

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.60

PhyloP100

2.8

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.12

REVEL

Benign

0.080

Sift

Benign

0.75

Sift4G

Benign

0.68

Polyphen

0.0040

Vest4

0.63

MutPred

0.39

Loss of loop (P = 0.0512)

MVP

0.13

MPC

0.076

ClinPred

0.14

GERP RS

3.5

Varity_R

0.095

gMVP

0.38

Mutation Taster

=92/8

polymorphism

(source)

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

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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