Variant 4-83075300-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_016129.3(COPS4):c.1091G>A(p.Arg364Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

COPS4
NM_016129.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.55

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37179476).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COPS4	NM_016129.3 linkuse as main transcript	c.1091G>A	p.Arg364Gln	missense_variant	10/10	ENST00000264389.7	NP_057213.2
COPS4	NM_001258006.2 linkuse as main transcript	c.1006G>A	p.Glu336Lys	missense_variant	9/9		NP_001244935.1
COPS4	NM_001330727.2 linkuse as main transcript	c.1239G>A	p.Thr413=	synonymous_variant	11/11		NP_001317656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COPS4	ENST00000264389.7 linkuse as main transcript	c.1091G>A	p.Arg364Gln	missense_variant	10/10	1	NM_016129.3	ENSP00000264389	P1	Q9BT78-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250310

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460786

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726640

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:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

Nov 28, 2023

The c.1091G>A (p.R364Q) alteration is located in exon 10 (coding exon 10) of the COPS4 gene. This alteration results from a G to A substitution at nucleotide position 1091, causing the arginine (R) at amino acid position 364 to be replaced by a glutamine (Q). 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

0.20

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.54

M_CAP

Benign

0.071

MetaRNN

Benign

0.37

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Vest4

0.35

MutPred

0.69

Gain of MoRF binding (P = 0.0112);

MVP

0.69

ClinPred

0.94

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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