dbSNP rs34343511: ORC6:p.Asp225Asp (chr16-46697501-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014321.4(ORC6):c.675T>C(p.Asp225Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,613,482 control chromosomes in the GnomAD database, including 565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 45 hom., cov: 33)

Exomes 𝑓: 0.024 ( 520 hom. )

Consequence

ORC6
NM_014321.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0550

Publications

9 publications found

Variant links:

Genes affected

ORC6 (HGNC:17151): (origin recognition complex subunit 6) 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. The protein encoded by this gene is a subunit of the ORC complex. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis. [provided by RefSeq, Oct 2010]

ORC6 Gene-Disease associations (from GenCC):

Meier-Gorlin syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
Meier-Gorlin syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ORC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 16-46697501-T-C is Benign according to our data. Variant chr16-46697501-T-C is described in ClinVar as Benign. ClinVar VariationId is 129866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.055 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0186 (2831/152268) while in subpopulation NFE AF = 0.0258 (1752/68018). AF 95% confidence interval is 0.0248. There are 45 homozygotes in GnomAd4. There are 1396 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 45 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014321.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORC6	NM_014321.4	MANE Select	c.675T>C	p.Asp225Asp	synonymous	Exon 7 of 7	NP_055136.1	Q9Y5N6
	ORC6	NR_037620.2		n.781T>C		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ORC6	ENST00000219097.7	TSL:1 MANE Select	c.675T>C	p.Asp225Asp	synonymous	Exon 7 of 7	ENSP00000219097.2	Q9Y5N6
ORC6	ENST00000912416.1		c.768T>C	p.Asp256Asp	synonymous	Exon 7 of 7	ENSP00000582475.1
ORC6	ENST00000912417.1		c.672T>C	p.Asp224Asp	synonymous	Exon 7 of 7	ENSP00000582476.1

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2833

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0390

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0186

AC:

4683

AN:

251270

AF XY:

0.0190

show subpopulations

Gnomad AFR exome

AF:

0.00302

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.0236

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.0259

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0241

AC:

35171

AN:

1461214

Hom.:

520

Cov.:

AF XY:

0.0238

AC XY:

17291

AN XY:

726926

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33472

American (AMR)

AF:

0.0122

AC:

546

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

570

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00468

AC:

404

AN:

86244

European-Finnish (FIN)

AF:

0.0341

AC:

1819

AN:

53414

Middle Eastern (MID)

AF:

0.0201

AC:

116

AN:

5766

European-Non Finnish (NFE)

AF:

0.0273

AC:

30341

AN:

1111390

Other (OTH)

AF:

0.0213

AC:

1286

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1783

3566

5348

7131

8914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1140

2280

3420

4560

5700

<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:

0.0186

AC:

2831

AN:

152268

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

1396

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00470

AC:

195

AN:

41532

American (AMR)

AF:

0.0201

AC:

308

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00497

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0390

AC:

414

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1752

AN:

68018

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0232

Hom.:

133

Bravo

AF:

0.0174

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0254

EpiControl

AF:

0.0244

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Meier-Gorlin syndrome 3 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.0

(source)

DANN

Benign

0.38

PhyloP100

-0.055

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over