Variant 4-83049256-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016129.3(COPS4):c.245A>G(p.Lys82Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,228 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COPS4
NM_016129.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.02

Variant links:

Genes affected

COPS4 (HGNC:16702): (COP9 signalosome subunit 4) This gene encodes one of eight subunits composing COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

COPS4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COPS4	NM_016129.3 linkuse as main transcript	c.245A>G	p.Lys82Arg	missense_variant	3/10	ENST00000264389.7	NP_057213.2
COPS4	NM_001330727.2 linkuse as main transcript	c.245A>G	p.Lys82Arg	missense_variant	3/11		NP_001317656.1
COPS4	NM_001258006.2 linkuse as main transcript	c.245A>G	p.Lys82Arg	missense_variant	3/9		NP_001244935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPS4	ENST00000264389.7 linkuse as main transcript	c.245A>G	p.Lys82Arg	missense_variant	3/10	1	NM_016129.3	ENSP00000264389	P1	Q9BT78-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460228

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726310

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.245A>G (p.K82R) alteration is located in exon 3 (coding exon 3) of the COPS4 gene. This alteration results from a A to G substitution at nucleotide position 245, causing the lysine (K) at amino acid position 82 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

.;T;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.2

M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.40

T;T;T;T

Polyphen

0.096, 0.99, 0.96

.;B;D;D

Vest4

0.71

MutPred

0.39

Loss of ubiquitination at K82 (P = 0.0107);Loss of ubiquitination at K82 (P = 0.0107);Loss of ubiquitination at K82 (P = 0.0107);Loss of ubiquitination at K82 (P = 0.0107);

MVP

0.69

MPC

1.2

ClinPred

0.96

GERP RS

4.5

Varity_R

0.37

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over