Variant 7-104165245-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002553.4(ORC5):c.1028A>T(p.Lys343Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000223 in 1,511,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ORC5
NM_002553.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.19

Variant links:

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]

ORC5 links:

ORC5 (HGNC:):

ORC5 links:

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ACMG classification

Classification made for transcript

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=0.07481697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORC5	NM_002553.4 linkuse as main transcript	c.1028A>T	p.Lys343Ile	missense_variant	11/14	ENST00000297431.9	NP_002544.1	O43913-1A4D0P7Q53FC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ORC5	ENST00000297431.9 linkuse as main transcript	c.1028A>T	p.Lys343Ile	missense_variant	11/14	1	NM_002553.4	ENSP00000297431.4	O43913-1
ORC5	ENST00000422497.5 linkuse as main transcript	n.*961A>T		non_coding_transcript_exon_variant	12/15	2		ENSP00000393208.1	G3V0H0
ORC5	ENST00000477223.1 linkuse as main transcript	n.490A>T		non_coding_transcript_exon_variant	1/4	2
ORC5	ENST00000422497.5 linkuse as main transcript	n.*961A>T		3_prime_UTR_variant	12/15	2		ENSP00000393208.1	G3V0H0

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000268

AC:

AN:

212616

Hom.:

AF XY:

0.000271

AC XY:

AN XY:

114562

show subpopulations

Gnomad AFR exome

AF:

0.000939

Gnomad AMR exome

AF:

0.000352

Gnomad ASJ exome

AF:

0.000567

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000558

GnomAD4 exome

AF:

0.000203

AC:

276

AN:

1358972

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

152

AN XY:

678388

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000391

Gnomad4 ASJ exome

AF:

0.000488

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000191

Gnomad4 OTH exome

AF:

0.000459

GnomAD4 genome

AF:

0.000400

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000357

Hom.:

Bravo

AF:

0.000480

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000232

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

The c.1028A>T (p.K343I) alteration is located in exon 11 (coding exon 11) of the ORC5 gene. This alteration results from a A to T substitution at nucleotide position 1028, causing the lysine (K) at amino acid position 343 to be replaced by an isoleucine (I). 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.4

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.29

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.48

MVP

0.49

MPC

0.57

ClinPred

0.060

GERP RS

5.0

Varity_R

0.50

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over