Variant 2-147958859-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181741.4(ORC4):c.233A>C(p.Asn78Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000903 in 1,107,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N78S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

ORC4
NM_181741.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.94

Variant links:

Genes affected

ORC4 (HGNC:8490): (origin recognition complex subunit 4) 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. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]

ORC4 links:

ORC4 (HGNC:):

ORC4 links:

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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	Protein	UniProt
ORC4	NM_181741.4 linkuse as main transcript	c.233A>C	p.Asn78Thr	missense_variant	5/14	ENST00000392857.10	NP_859525.1	O43929-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10 linkuse as main transcript	c.233A>C	p.Asn78Thr	missense_variant	5/14	1	NM_181741.4	ENSP00000376597.5		O43929-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000838

AC:

AN:

238644

Hom.:

AF XY:

0.00000776

AC XY:

AN XY:

128916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000594

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.03e-7

AC:

AN:

1107700

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

566666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

.;T;T;T;T;.;T

Eigen

Benign

0.0093

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

T;T;.;.;T;D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.54

D;D;D;D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

.;L;L;L;.;.;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

N;N;N;N;N;N;N

REVEL

Benign

0.083

Sift

Benign

0.12

T;T;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;.;T;.

Polyphen

0.36

.;B;B;B;.;.;.

Vest4

0.50

MutPred

0.39

.;Gain of ubiquitination at K73 (P = 0.143);Gain of ubiquitination at K73 (P = 0.143);Gain of ubiquitination at K73 (P = 0.143);Gain of ubiquitination at K73 (P = 0.143);Gain of ubiquitination at K73 (P = 0.143);Gain of ubiquitination at K73 (P = 0.143);

MVP

0.74

MPC

0.11

ClinPred

0.31

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over