dbSNP rs61756136: ORC1:p.Ser440Pro (chr1-52388507-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004153.4(ORC1):c.1318T>C(p.Ser440Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,614,188 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 8 hom. )

Consequence

ORC1
NM_004153.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.636

Publications

7 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057105124).

BP6

Variant 1-52388507-A-G is Benign according to our data. Variant chr1-52388507-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211798.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000735 (112/152330) while in subpopulation NFE AF = 0.000603 (41/68022). AF 95% confidence interval is 0.000457. There are 2 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1318T>C	p.Ser440Pro	missense	Exon 8 of 17	NP_004144.2
ORC1	NM_001190818.2		c.1318T>C	p.Ser440Pro	missense	Exon 8 of 17	NP_001177747.1	Q13415
ORC1	NM_001190819.2		c.1318T>C	p.Ser440Pro	missense	Exon 8 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.1318T>C	p.Ser440Pro	missense	Exon 8 of 17	ENSP00000360623.3	Q13415
ORC1	ENST00000371566.1	TSL:1	c.1318T>C	p.Ser440Pro	missense	Exon 8 of 17	ENSP00000360621.1	Q13415
ORC1	ENST00000959732.1		c.1318T>C	p.Ser440Pro	missense	Exon 7 of 16	ENSP00000629791.1

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00108

AC:

272

AN:

251478

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000765

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.000785

AC:

1147

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000809

AC XY:

588

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

33480

American (AMR)

AF:

0.00103

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

289

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000499

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0243

AC:

140

AN:

5758

European-Non Finnish (NFE)

AF:

0.000429

AC:

477

AN:

1111996

Other (OTH)

AF:

0.00197

AC:

119

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000735

AC:

112

AN:

152330

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41582

American (AMR)

AF:

0.000392

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68022

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00112

Hom.:

Bravo

AF:

0.000786

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000980

AC:

119

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00130

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Meier-Gorlin syndrome 1 (1)

not specified (1)

ORC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.011

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.38

M_CAP

Benign

0.019

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.64

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

REVEL

Benign

0.030

Sift

Benign

0.13

Sift4G

Benign

0.32

Polyphen

0.0040

Vest4

0.12

MVP

0.59

MPC

0.19

ClinPred

0.017

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.088

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

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

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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