rs73003466

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_181741.4(ORC4):c.604T>G(p.Leu202Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,606,864 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

ORC4
NM_181741.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.22

Publications

2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014760673).

BP6

Variant 2-147948209-A-C is Benign according to our data. Variant chr2-147948209-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159485.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00259 (394/152154) while in subpopulation AFR AF = 0.00888 (369/41564). AF 95% confidence interval is 0.00813. There are 1 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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
ORC4	NM_181741.4	MANE Select	c.604T>G	p.Leu202Val	missense	Exon 9 of 14	NP_859525.1
ORC4	NM_001190879.3		c.604T>G	p.Leu202Val	missense	Exon 10 of 15	NP_001177808.1
ORC4	NM_001374270.1		c.604T>G	p.Leu202Val	missense	Exon 11 of 16	NP_001361199.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ORC4	ENST00000392857.10	TSL:1 MANE Select	c.604T>G	p.Leu202Val	missense	Exon 9 of 14	ENSP00000376597.5
ORC4	ENST00000264169.6	TSL:5	c.604T>G	p.Leu202Val	missense	Exon 9 of 14	ENSP00000264169.2
ORC4	ENST00000535373.5	TSL:5	c.604T>G	p.Leu202Val	missense	Exon 10 of 15	ENSP00000441953.1

Frequencies

GnomAD3 genomes

AF:

0.00260

AC:

396

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000744

AC:

185

AN:

248794

AF XY:

0.000549

show subpopulations

Gnomad AFR exome

AF:

0.0101

Gnomad AMR exome

AF:

0.000642

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000282

AC:

410

AN:

1454710

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

164

AN XY:

723988

show subpopulations

African (AFR)

AF:

0.0101

AC:

335

AN:

33198

American (AMR)

AF:

0.000630

AC:

AN:

44416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000585

AC:

AN:

85522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.00000632

AC:

AN:

1107022

Other (OTH)

AF:

0.000566

AC:

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00259

AC:

394

AN:

152154

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00888

AC:

369

AN:

41564

American (AMR)

AF:

0.00124

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67916

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000857

Hom.:

Bravo

AF:

0.00309

ESP6500AA

AF:

0.00864

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Meier-Gorlin syndrome 2 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.5

PhyloP100

1.2

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.70

MVP

0.92

MPC

0.41

ClinPred

0.094

GERP RS

0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.55

gMVP

0.62

Mutation Taster

=43/57

disease causing

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over