rs749495781

Variant names:

• chr7-104184015-C-A
• rs749495781
• NM_002553.4:c.752G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-104184015-C-A
• chr7-104184015-C-T

Variant summary

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

The NM_002553.4(ORC5):​c.752G>T​(p.Arg251Leu) variant causes a missense change. 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. R251H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ORC5 NM_002553.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.11

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]

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 rank	MANE	Protein	UniProt
ORC5	NM_002553.4	c.752G>T	p.Arg251Leu	missense_variant	Exon 8 of 14	ENST00000297431.9	NP_002544.1
ORC5	NM_181747.4	c.752G>T	p.Arg251Leu	missense_variant	Exon 8 of 9		NP_859531.1
ORC5	XM_047420431.1	c.684+4236G>T		intron_variant	Intron 6 of 7		XP_047276387.1
ORC5	XM_011516273.4	c.*3899G>T		downstream_gene_variant			XP_011514575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC5	ENST00000297431.9	c.752G>T	p.Arg251Leu	missense_variant	Exon 8 of 14	1	NM_002553.4	ENSP00000297431.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	0.031
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.16
Sift	Benign	0.30	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.30	B;P
Vest4		0.79
MutPred		0.50		Loss of MoRF binding (P = 0.0093);Loss of MoRF binding (P = 0.0093);
MVP		0.27
MPC		0.11
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.42
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs749495781; hg19: chr7-103824463;