7-104166864-C-G

Variant names:

• chr7-104166864-C-G
• rs141275662
• NM_002553.4:c.898G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 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 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20501721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORC5	NM_002553.4	c.898G>C	p.Val300Leu	missense_variant	Exon 10 of 14	ENST00000297431.9	NP_002544.1
ORC5	XM_047420431.1	c.*44G>C		3_prime_UTR_variant	Exon 8 of 8		XP_047276387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC5	ENST00000297431.9	c.898G>C	p.Val300Leu	missense_variant	Exon 10 of 14	1	NM_002553.4	ENSP00000297431.4
ORC5	ENST00000422497.5	n.*831G>C		non_coding_transcript_exon_variant	Exon 11 of 15	2		ENSP00000393208.1
ORC5	ENST00000422497.5	n.*831G>C		3_prime_UTR_variant	Exon 11 of 15	2		ENSP00000393208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250676 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135438

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 SAS 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: 5 AN: 1454172 Hom.: 0 Cov.: 27 AF XY: 0.00000414 AC XY: 3 AN XY: 723882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.63
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.080
Sift	Benign	0.75	T
Sift4G	Benign	0.68	T
Polyphen		0.0040	B
Vest4		0.63
MutPred		0.39		Loss of loop (P = 0.0512);
MVP		0.13
MPC		0.076
ClinPred		0.14	T
GERP RS		3.5
Varity_R		0.095
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs141275662; hg19: chr7-103807312;