17-17248951-G-C

Variant names:

• chr17-17248951-G-C
• rs775388275
• NM_003653.4:c.1112C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003653.4(COPS3):​c.1112C>G​(p.Ala371Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,453,030 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: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: COPS3 NM_003653.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4016046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPS3	NM_003653.4	c.1112C>G	p.Ala371Gly	missense_variant	Exon 10 of 12	ENST00000268717.10	NP_003644.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPS3	ENST00000268717.10	c.1112C>G	p.Ala371Gly	missense_variant	Exon 10 of 12	1	NM_003653.4	ENSP00000268717.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1453030 Hom.: 0 Cov.: 29 AF XY: 0.00000830 AC XY: 6 AN XY: 722954

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: 0.0000163

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1112C>G (p.A371G) alteration is located in exon 10 (coding exon 10) of the COPS3 gene. This alteration results from a C to G substitution at nucleotide position 1112, causing the alanine (A) at amino acid position 371 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;T;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.90	.;.;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N;.;N;.
REVEL	Benign	0.16
Sift	Benign	0.17	T;.;T;.
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0070	.;.;B;.
Vest4		0.59
MutPred		0.36		.;.;Gain of disorder (P = 0.0994);.;
MVP		0.58
MPC		0.57
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs775388275; hg19: chr17-17152265;