dbSNP rs3768686: ORC4:c.*303A>G (chr2-147935207-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181741.4(ORC4):c.*303A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 315,970 control chromosomes in the GnomAD database, including 20,264 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8436 hom., cov: 32)

Exomes 𝑓: 0.36 ( 11828 hom. )

Consequence

ORC4
NM_181741.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.30

Publications

12 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORC4	NM_181741.4 link	c.*303A>G		3_prime_UTR_variant	Exon 14 of 14	ENST00000392857.10	NP_859525.1	O43929-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORC4	ENST00000392857.10 link	c.*303A>G		3_prime_UTR_variant	Exon 14 of 14	1	NM_181741.4	ENSP00000376597.5		O43929-1

Frequencies

GnomAD3 genomes

AF:

0.301

AC:

45653

AN:

151888

Hom.:

8426

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0874

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.511

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.375

Gnomad OTH

AF:

0.269

GnomAD4 exome

AF:

0.361

AC:

59222

AN:

163964

Hom.:

11828

Cov.:

AF XY:

0.370

AC XY:

31884

AN XY:

86276

show subpopulations

African (AFR)

AF:

0.0813

AC:

443

AN:

5448

American (AMR)

AF:

0.326

AC:

2146

AN:

6578

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

1076

AN:

4942

East Asian (EAS)

AF:

0.373

AC:

3453

AN:

9266

South Asian (SAS)

AF:

0.439

AC:

9065

AN:

20630

European-Finnish (FIN)

AF:

0.468

AC:

3560

AN:

7606

Middle Eastern (MID)

AF:

0.176

AC:

120

AN:

680

European-Non Finnish (NFE)

AF:

0.362

AC:

36076

AN:

99544

Other (OTH)

AF:

0.354

AC:

3283

AN:

9270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1736

3472

5207

6943

8679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.301

AC:

45680

AN:

152006

Hom.:

8436

Cov.:

AF XY:

0.312

AC XY:

23188

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0871

AC:

3616

AN:

41514

American (AMR)

AF:

0.340

AC:

5182

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

794

AN:

3466

East Asian (EAS)

AF:

0.378

AC:

1951

AN:

5156

South Asian (SAS)

AF:

0.475

AC:

2287

AN:

4810

European-Finnish (FIN)

AF:

0.511

AC:

5395

AN:

10560

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.375

AC:

25472

AN:

67942

Other (OTH)

AF:

0.275

AC:

579

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1480

2960

4439

5919

7399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.327

Hom.:

10388

Bravo

AF:

0.272

Asia WGS

AF:

0.454

AC:

1574

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.38

(source)

DANN

Benign

0.69

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over