chr17-17270991-A-T

Variant names:

• chr17-17270991-A-T
• NM_003653.4:c.203T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001316356.2(COPS3):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: COPS3 NM_001316356.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 64 codons. Genomic position: 17267935. Lost 0.177 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316356.2. 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
	COPS3	NM_003653.4	MANE Select	c.203T>A	p.Met68Lys	missense	Exon 3 of 12	NP_003644.2
	COPS3	NM_001316356.2		c.2T>A	p.Met1?	start_lost	Exon 2 of 11	NP_001303285.1
	COPS3	NM_001199125.1		c.143T>A	p.Met48Lys	missense	Exon 3 of 12	NP_001186054.1	Q9UNS2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COPS3	ENST00000268717.10	TSL:1 MANE Select	c.203T>A	p.Met68Lys	missense	Exon 3 of 12	ENSP00000268717.5	Q9UNS2-1
	COPS3	ENST00000954596.1		c.203T>A	p.Met68Lys	missense	Exon 3 of 12	ENSP00000624655.1
	COPS3	ENST00000954594.1		c.203T>A	p.Met68Lys	missense	Exon 3 of 12	ENSP00000624653.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		9.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.27
Sift	Benign	0.95	T
Sift4G	Benign	0.93	T
Polyphen		0.0010	B
Vest4		0.88
MutPred		0.53		Gain of ubiquitination at M68 (P = 0.017)
MVP		0.70
MPC		0.88
ClinPred		0.80	D
GERP RS		5.5
PromoterAI		-0.020	Neutral
Varity_R		0.57
gMVP		0.71

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

Other links and lift over

hg19: chr17-17174305;