1-52396199-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004153.4(ORC1):c.568G>A(p.Val190Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,614,110 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 101 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 93 hom. )

Consequence

ORC1
NM_004153.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.03

Publications

5 publications found

Variant links:

Genes affected

ORC1 (HGNC:8487): (origin recognition complex subunit 1) The origin recognition complex (ORC) is a highly conserved six subunits 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 the largest subunit of the ORC complex. While other ORC subunits are stable throughout the cell cycle, the levels of this protein vary during the cell cycle, which has been shown to be controlled by ubiquitin-mediated proteolysis after initiation of DNA replication. This protein is found to be selectively phosphorylated during mitosis. It is also reported to interact with MYST histone acetyltransferase 2 (MyST2/HBO1), a protein involved in control of transcription silencing. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

ORC1 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Meier-Gorlin syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020616055).

BP6

Variant 1-52396199-C-T is Benign according to our data. Variant chr1-52396199-C-T is described in ClinVar as Benign. ClinVar VariationId is 129863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004153.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC1	NM_004153.4	MANE Select	c.568G>A	p.Val190Met	missense	Exon 5 of 17	NP_004144.2
ORC1	NM_001190818.2		c.568G>A	p.Val190Met	missense	Exon 5 of 17	NP_001177747.1	Q13415
ORC1	NM_001190819.2		c.568G>A	p.Val190Met	missense	Exon 5 of 17	NP_001177748.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC1	ENST00000371568.8	TSL:1 MANE Select	c.568G>A	p.Val190Met	missense	Exon 5 of 17	ENSP00000360623.3	Q13415
ORC1	ENST00000371566.1	TSL:1	c.568G>A	p.Val190Met	missense	Exon 5 of 17	ENSP00000360621.1	Q13415
ORC1	ENST00000959732.1		c.568G>A	p.Val190Met	missense	Exon 4 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3225

AN:

152110

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00565

AC:

1422

AN:

251492

AF XY:

0.00413

show subpopulations

Gnomad AFR exome

AF:

0.0745

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00219

AC:

3208

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1349

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0722

AC:

2418

AN:

33480

American (AMR)

AF:

0.00418

AC:

187

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000243

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000138

AC:

154

AN:

1112002

Other (OTH)

AF:

0.00566

AC:

342

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

204

408

611

815

1019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0212

AC:

3233

AN:

152228

Hom.:

101

Cov.:

AF XY:

0.0203

AC XY:

1513

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0723

AC:

3003

AN:

41520

American (AMR)

AF:

0.0102

AC:

156

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68020

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

161

322

482

643

804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0111

Hom.:

Bravo

AF:

0.0248

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0735

AC:

324

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00690

AC:

838

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Meier-Gorlin syndrome 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.12

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.011

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

-2.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.020

REVEL

Benign

0.040

Sift

Benign

0.18

Sift4G

Benign

0.15

Polyphen

0.14

Vest4

0.048

MVP

0.35

MPC

0.16

ClinPred

0.0032

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over