rs2307394

Positions:

• chr2-147958859-T-A
• chr2-147958859-T-C
• chr2-147958859-T-G

Variant summary

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

The NM_181741.4(ORC4):​c.233A>T​(p.Asn78Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ORC4 NM_181741.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

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]

ACMG classification

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	c.233A>T	p.Asn78Ile	missense_variant	5/14	ENST00000392857.10	NP_859525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10	c.233A>T	p.Asn78Ile	missense_variant	5/14	1	NM_181741.4	ENSP00000376597.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.094	.;T;T;T;T;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T;D;.;.;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.1	.;M;M;M;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.016	D;D;D;D;D;D;D
Sift4G	Benign	0.062	T;T;T;T;.;T;.
Polyphen		0.40	.;B;B;B;.;.;.
Vest4		0.73
MutPred		0.44		.;Gain of methylation at K82 (P = 0.0657);Gain of methylation at K82 (P = 0.0657);Gain of methylation at K82 (P = 0.0657);Gain of methylation at K82 (P = 0.0657);Gain of methylation at K82 (P = 0.0657);Gain of methylation at K82 (P = 0.0657);
MVP		0.87
MPC		0.15
ClinPred		0.91	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs2307394; hg19: chr2-148716428;