7-104195199-C-G

Variant names:

• chr7-104195199-C-G
• rs374359658
• NM_002553.4:c.497G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002553.4(ORC5):​c.497G>C​(p.Arg166Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R166H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ORC5 NM_002553.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15
• Publications: 0 publications found

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

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, 0.836

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.497G>C	p.Arg166Pro	missense	Exon 5 of 14	NP_002544.1	O43913-1
	ORC5	NM_181747.4		c.497G>C	p.Arg166Pro	missense	Exon 5 of 9	NP_859531.1	O43913-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC5	ENST00000297431.9	TSL:1 MANE Select	c.497G>C	p.Arg166Pro	missense	Exon 5 of 14	ENSP00000297431.4	O43913-1
	ORC5	ENST00000447452.6	TSL:1	c.497G>C	p.Arg166Pro	missense	Exon 5 of 9	ENSP00000395747.2	O43913-2
	ORC5	ENST00000938620.1		c.497G>C	p.Arg166Pro	missense	Exon 5 of 15	ENSP00000608679.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000165 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.38
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.97	D
Vest4		0.87
MutPred		0.57		Gain of helix (P = 0.0325)
MVP		0.84
MPC		0.43
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.88
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs374359658; hg19: chr7-103835647;