2-147958859-T-C

Variant names:

Variant summary

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

The NM_181741.4(ORC4):c.233A>G(p.Asn78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,254,158 control chromosomes in the GnomAD database, including 64,339 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 0.33 ( 8278 hom., cov: 32)

Exomes 𝑓: 0.31 ( 56061 hom. )

Consequence

ORC4
NM_181741.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.94

Publications

79 publications found

Variant links:

Genes affected

ORC4 (HGNC:8490): (origin recognition complex subunit 4) 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. This gene encodes a subunit of the ORC complex. Several alternatively spliced transcript variants, some of which encode the same protein, have been reported for this gene. [provided by RefSeq, Oct 2010]

ORC4 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Meier-Gorlin syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORC4 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=0.0019708276).

BP6

Variant 2-147958859-T-C is Benign according to our data. Variant chr2-147958859-T-C is described in ClinVar as Benign. ClinVar VariationId is 159483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181741.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC4	NM_181741.4	MANE Select	c.233A>G	p.Asn78Ser	missense	Exon 5 of 14	NP_859525.1	O43929-1
ORC4	NM_001190879.3		c.233A>G	p.Asn78Ser	missense	Exon 6 of 15	NP_001177808.1	O43929-1
ORC4	NM_001374270.1		c.233A>G	p.Asn78Ser	missense	Exon 7 of 16	NP_001361199.1	O43929-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC4	ENST00000392857.10	TSL:1 MANE Select	c.233A>G	p.Asn78Ser	missense	Exon 5 of 14	ENSP00000376597.5	O43929-1
ORC4	ENST00000877934.1		c.233A>G	p.Asn78Ser	missense	Exon 5 of 15	ENSP00000547993.1
ORC4	ENST00000264169.6	TSL:5	c.233A>G	p.Asn78Ser	missense	Exon 5 of 14	ENSP00000264169.2	O43929-1

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49342

AN:

151556

Hom.:

8273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.274

Gnomad AMR

AF:

0.382

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.349

GnomAD2 exomes

AF:

0.357

AC:

85198

AN:

238644

AF XY:

0.351

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.460

Gnomad ASJ exome

AF:

0.347

Gnomad EAS exome

AF:

0.530

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.319

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.313

AC:

345400

AN:

1102484

Hom.:

56061

Cov.:

AF XY:

0.313

AC XY:

176816

AN XY:

564144

show subpopulations

African (AFR)

AF:

0.292

AC:

7704

AN:

26418

American (AMR)

AF:

0.453

AC:

19744

AN:

43602

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8030

AN:

23744

East Asian (EAS)

AF:

0.504

AC:

18890

AN:

37472

South Asian (SAS)

AF:

0.319

AC:

24534

AN:

77008

European-Finnish (FIN)

AF:

0.335

AC:

17647

AN:

52620

Middle Eastern (MID)

AF:

0.429

AC:

2122

AN:

4948

European-Non Finnish (NFE)

AF:

0.293

AC:

231398

AN:

788450

Other (OTH)

AF:

0.318

AC:

15331

AN:

48222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

10523

21047

31570

42094

52617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6502

13004

19506

26008

32510

<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:

0.326

AC:

49390

AN:

151674

Hom.:

8278

Cov.:

AF XY:

0.327

AC XY:

24269

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.298

AC:

12354

AN:

41408

American (AMR)

AF:

0.382

AC:

5819

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

1137

AN:

3468

East Asian (EAS)

AF:

0.513

AC:

2655

AN:

5174

South Asian (SAS)

AF:

0.319

AC:

1535

AN:

4818

European-Finnish (FIN)

AF:

0.333

AC:

3501

AN:

10498

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.314

AC:

21288

AN:

67756

Other (OTH)

AF:

0.347

AC:

731

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1704

3408

5112

6816

8520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<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:

0.322

Hom.:

38169

Bravo

AF:

0.333

TwinsUK

AF:

0.304

AC:

1128

ALSPAC

AF:

0.299

AC:

1153

ESP6500AA

AF:

0.309

AC:

1354

ESP6500EA

AF:

0.313

AC:

2678

ExAC

AF:

0.345

AC:

41728

Asia WGS

AF:

0.354

AC:

1223

AN:

3450

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Meier-Gorlin syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

Eigen

Benign

-0.17

Eigen_PC

Benign

0.031

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.2

PhyloP100

2.9

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

REVEL

Benign

0.040

Sift

Benign

0.091

Sift4G

Benign

0.27

Polyphen

0.021

Vest4

0.25

MPC

0.074

ClinPred

0.0086

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.24

Mutation Taster

=294/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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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