Genetic Variant COPS3:p.Ala2Ala (chr17-17281181-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4BP6_ModerateBP7BS2

The NM_003653.4(COPS3):c.6G>A(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,610,870 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 22 hom. )

Consequence

COPS3
NM_003653.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.68

Publications

5 publications found

Variant links:

Genes affected

COPS3 (HGNC:2239): (COP9 signalosome subunit 3) The protein encoded by this gene possesses kinase activity that phosphorylates regulators involved in signal transduction. It phosphorylates I kappa-Balpha, p105, and c-Jun. It acts as a docking site for complex-mediated phosphorylation. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

COPS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.12).

BP6

Variant 17-17281181-C-T is Benign according to our data. Variant chr17-17281181-C-T is described in ClinVar as Benign. ClinVar VariationId is 708422.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.67 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003653.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COPS3	NM_003653.4	MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 12	NP_003644.2
COPS3	NM_001316355.2		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 11	NP_001303284.1
COPS3	NM_001316356.2		c.-66G>A		5_prime_UTR	Exon 1 of 11	NP_001303285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COPS3	ENST00000268717.10	TSL:1 MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 12	ENSP00000268717.5	Q9UNS2-1
COPS3	ENST00000954596.1		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 12	ENSP00000624655.1
COPS3	ENST00000954594.1		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 12	ENSP00000624653.1

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00581

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00346

AC:

840

AN:

242858

AF XY:

0.00352

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.00729

Gnomad EAS exome

AF:

0.000220

Gnomad FIN exome

AF:

0.000957

Gnomad NFE exome

AF:

0.00563

Gnomad OTH exome

AF:

0.00388

GnomAD4 exome

AF:

0.00514

AC:

7504

AN:

1458692

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

3614

AN XY:

725404

show subpopulations

African (AFR)

AF:

0.000957

AC:

AN:

33430

American (AMR)

AF:

0.00194

AC:

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.00834

AC:

216

AN:

25908

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.000655

AC:

AN:

85558

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

53004

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00600

AC:

6667

AN:

1110796

Other (OTH)

AF:

0.00621

AC:

374

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

388

776

1165

1553

1941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.00348

AC:

530

AN:

152178

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000891

AC:

AN:

41530

American (AMR)

AF:

0.00268

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00104

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00579

AC:

394

AN:

67990

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

118

148

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:

0.00558

Hom.:

Bravo

AF:

0.00369

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

1.7

PromoterAI

-0.51

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

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