chr7-104195199-C-T

Variant names:

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

Variant summary

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

The NM_002553.4(ORC5):​c.497G>A​(p.Arg166His) variant causes a missense change. The variant allele was found at a frequency of 0.0000388 in 1,574,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ORC5 NM_002553.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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.497G>A	p.Arg166His	missense_variant	Exon 5 of 14	ENST00000297431.9	NP_002544.1
ORC5	NM_181747.4	c.497G>A	p.Arg166His	missense_variant	Exon 5 of 9		NP_859531.1
ORC5	XM_011516273.4	c.497G>A	p.Arg166His	missense_variant	Exon 5 of 7		XP_011514575.1
ORC5	XM_047420431.1	c.497G>A	p.Arg166His	missense_variant	Exon 5 of 8		XP_047276387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC5	ENST00000297431.9	c.497G>A	p.Arg166His	missense_variant	Exon 5 of 14	1	NM_002553.4	ENSP00000297431.4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000468 AC: 10 AN: 213890 Hom.: 0 AF XY: 0.0000601 AC XY: 7 AN XY: 116458

Gnomad AFR exome AF: 0.0000736

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000848

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.0000295

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000380 AC: 54 AN: 1422112 Hom.: 0 Cov.: 28 AF XY: 0.0000368 AC XY: 26 AN XY: 706632

Gnomad4 AFR exome AF: 0.0000650

Gnomad4 AMR exome AF: 0.0000277

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000115

Gnomad4 FIN exome AF: 0.0000941

Gnomad4 NFE exome AF: 0.0000301

Gnomad4 OTH exome AF: 0.0000679

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74240

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497G>A (p.R166H) alteration is located in exon 5 (coding exon 5) of the ORC5 gene. This alteration results from a G to A substitution at nucleotide position 497, causing the arginine (R) at amino acid position 166 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.49	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.99	D;D
Vest4		0.77
MVP		0.79
MPC		0.38
ClinPred		0.43	T
GERP RS		5.7
Varity_R		0.50
gMVP		0.72

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: rs374359658; hg19: chr7-103835647;