dbSNP rs28381552: ORC3:c.*208T>C (chr6-87667331-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_012381.4(ORC3):c.*208T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 428,988 control chromosomes in the GnomAD database, including 377 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 0.032 ( 98 hom., cov: 32)

Exomes 𝑓: 0.039 ( 279 hom. )

Consequence

ORC3
NM_012381.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.106

Publications

10 publications found

Variant links:

Genes affected

ORC3 (HGNC:8489): (origin recognition complex subunit 3) 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 a subunit of the ORC complex. Studies of a similar gene in Drosophila suggested a possible role of this protein in neuronal proliferation and olfactory memory. Alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene. [provided by RefSeq, Jul 2008]

ORC3 links:

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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=-0.85).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0316 (4815/152312) while in subpopulation NFE AF = 0.0472 (3208/68018). AF 95% confidence interval is 0.0458. There are 98 homozygotes in GnomAd4. There are 2275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 98 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012381.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ORC3	NM_012381.4	MANE Select	c.*208T>C	3_prime_UTR	Exon 20 of 20	NP_036513.2
ORC3	NM_181837.3		c.*208T>C	3_prime_UTR	Exon 20 of 20	NP_862820.1	Q9UBD5-2
ORC3	NM_001197259.2		c.*208T>C	3_prime_UTR	Exon 19 of 19	NP_001184188.1	Q9UBD5-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ORC3	ENST00000392844.8	TSL:1 MANE Select	c.*208T>C	3_prime_UTR	Exon 20 of 20	ENSP00000376586.3	Q9UBD5-1
ORC3	ENST00000257789.4	TSL:1	c.*208T>C	3_prime_UTR	Exon 20 of 20	ENSP00000257789.4	Q9UBD5-2
ORC3	ENST00000911372.1		c.*208T>C	3_prime_UTR	Exon 20 of 20	ENSP00000581431.1

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4819

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00731

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.0386

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.0206

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0472

Gnomad OTH

AF:

0.0421

GnomAD4 exome

AF:

0.0394

AC:

10909

AN:

276676

Hom.:

279

Cov.:

AF XY:

0.0394

AC XY:

5600

AN XY:

142032

show subpopulations

African (AFR)

AF:

0.00927

AC:

AN:

7766

American (AMR)

AF:

0.0394

AC:

337

AN:

8548

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

211

AN:

9750

East Asian (EAS)

AF:

0.0208

AC:

473

AN:

22772

South Asian (SAS)

AF:

0.0152

AC:

173

AN:

11348

European-Finnish (FIN)

AF:

0.0226

AC:

478

AN:

21194

Middle Eastern (MID)

AF:

0.0373

AC:

AN:

1394

European-Non Finnish (NFE)

AF:

0.0477

AC:

8387

AN:

175936

Other (OTH)

AF:

0.0404

AC:

726

AN:

17968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

485

970

1454

1939

2424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0316

AC:

4815

AN:

152312

Hom.:

Cov.:

AF XY:

0.0305

AC XY:

2275

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00729

AC:

303

AN:

41572

American (AMR)

AF:

0.0385

AC:

589

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3470

East Asian (EAS)

AF:

0.0150

AC:

AN:

5186

South Asian (SAS)

AF:

0.0213

AC:

103

AN:

4828

European-Finnish (FIN)

AF:

0.0206

AC:

219

AN:

10614

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0472

AC:

3208

AN:

68018

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

247

494

740

987

1234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0418

Hom.:

279

Bravo

AF:

0.0329

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.1

(source)

DANN

Benign

0.49

PhyloP100

-0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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